Aryl or heteroaryl derivative

ABSTRACT

A compound indicated by formula (I) or a pharmacologically acceptable salt thereof is provided as a compound that can be a therapeutic or prophylactic drug for TRPC6-related diseases, such as nephrotic syndrome, membranous nephropathy, acute renal failure, septicemia, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, and muscular dystrophy. (In the formula, Ar1, Ar2, X1-X3, R1, R3, R7, R8, L1, and L2 are as defined in the specifications.)

TECHNICAL FIELD

The present invention relates to aryl or heteroaryl derivatives useful as pharmaceutical agents. More specifically, the present invention relates to aryl or heteroaryl derivatives or pharmaceutically acceptable salts thereof useful for the treatment or prevention of diseases in which a TRPC6 inhibitor may be involved, such as nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, or muscular dystrophy.

BACKGROUND ART

The TRPC6 channel, a member of the Transient receptor potential (TRP) family, which is a non-selective cation-permeable channel, is activated by diacylglycerol and the like produced by activation of phospholipase C and exerts physiological and pathophysiological effects. TRPC6 has effects such as pathological cardiac hypertrophy and fibrosis, progression of myocardial damage in muscular dystrophy, acute pulmonary vasoconstriction, pathological progression associated with chronic hypoxia-induced pulmonary hypertension, allergic immune response, migration of cells such as neutrophils, increased endothelial permeability on inflammation, pathological flattening of podocytes foot processes and following progression of glomerular injury, and proliferation or infiltration of malignant tumors, and is diversely distributed in the brain, heart, lungs, kidneys, placenta, ovaries, spleen, and the like (NPLs 1 to 13). In familial focal segmental glomerulosclerosis (FSGS), a gain-of-function mutant of TRPC6 has been identified, and in idiopathic nephrotic syndrome or idiopathic pulmonary arterial hypertension patients, a variant in the promoter region that increases mRNA expression of TRPC6 has been identified. Thus, it is considered that enhanced activation or increased expression of TRPC6 contributes to pathological progression of nephrotic syndrome, pulmonary hypertension, and the like (NPLs 14 to 22). Furthermore, increased expression of TRPC6 has been reported in minimal change nephrotic syndrome, membranous nephropathy, and diabetic nephropathy (NPLs 23 to 24). Thus, TRPC6 inhibitors, which inhibit ion influx via the TRPC6 channel, are expected to be useful for prevention and/or treatment of such as nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, muscular dystrophy or the like. Compounds inhibiting TRPC6 are described in PLTs 1 to 11.

CITATION LIST Patent Literature

-   [PTL 1] WO2011/107474 -   [PTL 2] WO2012/037349 -   [PTL 3] WO2012/037351 -   [PTL 4] WO2014/016766 -   [PTL 5] Chinese Patent Application Publication No. 104292233 -   [PTL 6] Chinese Patent Application Publication No. 106317050 -   [PTL 7] Chinese Patent Application Publication No. 107253952 -   [PTL 8] WO2019/079578 -   [PTL 9] WO2019/081637 -   [PTL 10] WO2019/158572 -   [PTL 11] WO2019/161010

Non Patent Literature

-   [NPL 1] J. Clin. Invest. 116: 3114-3126, 2006 -   [NPL 2] Dev. Cell. 23: 705-715, 2012 -   [NPL 3] Circ. Res. 114: 823-832, 2014 -   [NPL 4] Proc. Natl. Acd. Sci. USA 103: 19093-19098, 2006 -   [NPL 5] J. Cardiovasc. Pharmacol. 57: 140-147, 2011 -   [NPL 6] Hypertension 63: 173-80, 2014 -   [NPL 7] Clin. Exp. Allergy 38: 1548-1558, 2008 -   [NPL 8] Acta. Physiol. 195: 3-11, 2009 -   [NPL 9] J. Exp. Med. 209: 1953-1968, 2011 -   [NPL 10] Arterioscler. Thromb. Vasc. Biol. 33: 2121-2129, 2013 -   [NPL 11] PLoS ONE 5: e12859, 2010 -   [NPL 12] Expert. Opin. Ther. Targets. 14: 513-27, 2010 -   [NPL 13] BMC Cancer 13:116, 2013 -   [NPL 14] Science 308: 1801-1804, 2005 -   [NPL 15] Nat. Genet. 37: 739-744, 2005 -   [NPL 16] PLoS One 4: e7771, 2009 -   [NPL 17] Clin. J. Am. Soc. Nephrol. 6: 1139-1148, 2011 -   [NPL 18] Mol. Biol. Cell. 22: 1824-1835, 2011 -   [NPL 19] BMC Nephrol. 14:104, 2013 -   [NPL 20] Pediatr. Res. 74: 511-516, 2013 -   [NPL 21] Nephrol. Dial. Transplant. 28: 1830-1838, 2013 -   [NPL 22] Circulation 119: 2313-2322, 2009 -   [NPL 23] J. Am. Soc. Nephrol. 18: 29-36, 2007 -   [NPL 24] Mol Immunol. February; 94:75-81, 2018.

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a novel compound having a TRPC6-inhibitory effect or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound, and a therapeutic agent or prophylactic agent for diseases associated with TRPC6.

Solution to Problem

As a result of diligent studies for the above-mentioned purpose, the present inventors arrived at the following invention.

[1] A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[wherein,

X¹, X², and X³ are independently CH, N, or CY;

At least one of X¹, X², and X³ is CH or CY;

Y is a halogen atom, or a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms;

R¹ is a cyano group, a fluorine atom, or a chlorine atom;

L¹ is —O—, —S—, —SO—, —CH(R¹¹)—, —C(═CH₂)—, —CO—, 1,1-cyclopropylidene group, or —NR¹²—;

R¹¹ is a hydrogen atom, a hydroxy group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, or a C₁₋₃ alkoxy group optionally substituted with 1 to 2 cyano groups;

R¹² is a hydrogen atom, or a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms;

Ar¹ is a nitrogen-containing heteroaryl ring optionally substituted with 1 to 3 R².

R² is independently a halogen atom, a cyano group, or a C₁₋₄ alkyl group optionally substituted with 1 to 3 halogen atoms;

R³ is a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, a (C₁₋₃ alkylcarbonyl)amino group, a (C₁₋₆ alkylamino)carbonyl group, a di(C₁₋₃ alkyl)aminocarbonyl group, a (C₁₋₃ alkoxy)carbonyl group, a (C₃₋₈ cycloalkyl)amino group, a (C₃₋₈ heterocycloalkyl)amino group, a C₃₋₈ cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C₃₋₈ cycloalkyloxy group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkyl group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkoxy group optionally substituted with 1 to 6 R³, a di(C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a (C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R³², an aryl group optionally substituted with 1 to 4 R³², or a heteroaryl group optionally substituted with 1 to 4 R³²;

R³¹ is independently a halogen atom, a hydroxy group, a cyclopropylidene group, a C₃₋₈ cycloalkyl group optionally substituted with 1 to 3 halogen atoms, a 3- to 8-membered heterocycloalkyl group, an oxetanylidene group, a C₁₋₄ alkoxy group, or a 3- to 8-membered cycloalkyloxy group;

R³² is independently a halogen atom, a hydroxy group, an acetylamino group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₁₋₃ alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, a cyano group, a carboxy group, a (C₁₋₃ alkoxy)carbonyl group, a (C₁₋₃ alkyl)sulfonyl group, a carboxamide group, or a benzyloxy group;

when R² and R³ are bonded to atoms adjacent to each other on Ar¹, R² and R³ may be bonded via a single bond or —O— to form a 5- to 7-membered ring together with the atoms of Ar¹ to which they are bonded;

Ar² is an aryl ring optionally substituted with 1 to 4 R⁴, or a heteroaryl ring optionally substituted with 1 to 4 R⁴;

R⁴ is independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C₁₋₃ alkyl)amino group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, or C₁₋₃ alkoxy group;

L² is a single bond, a C₁₋₆ alkylene group optionally substituted with 1 to 3 R²¹, a C₃₋₈ cycloalkylene group optionally substituted with 1 to 3 R²¹, or a 4- to 8-membered heterocycloalkylene group optionally substituted with 1 to 3 R²¹;

L² may be bonded at any position to Ar² or —NR⁷R⁸ which is located at either end of it;

One sp³ carbon atom at any position of L² may be replaced by a structure of —O or —NR²²—;

R²¹ is independently a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, a C₁₋₆ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₃₋₈ cycloalkyl group, a C₁₋₆ alkoxy group, a (C₁₋₃ alkoxy)C₁₋₃ alkyl group, a (C₁₋₃ alkoxy)C₁₋₃ alkoxy group, a (hydroxy) C₁₋₆ alkyl group, a (carboxy)C₁₋₃ alkyl group, a (carboxy)C₁₋₃ alkoxy group, a (C₁₋₃ alkoxy)carbonyl group, a (C₁₋₃ alkoxycarbonyl)C₁₋₃ alkyl group, a (C₁₋₆ alkylamino)carbonyl group, a di(C₁₋₃ alkyl) aminocarbonyl group, a phenyl group optionally substituted with 1 to 3 halogen atoms, a heteroaryl group optionally substituted with 1 to 3 halogen atoms, or a phenoxy group optionally substituted with 1 to 3 halogen atoms;

R²² is a hydrogen atom or a C₁₋₃ alkyl group;

L² and R⁷ may be bonded via a single bond, —O—, —S(═O)_(n)—, or —NR²³— to form a 4- to 8-membered ring containing a nitrogen atom to which L² and R⁷ are bonded, and the ring is optionally substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups;

n represents an integer from 0 to 2;

R²³ is a hydrogen atom or a C₁₋₃ alkyl group;

when L² and R⁴ are bonded to atoms adjacent to each other on Ar², they may be bonded via a single-bond or —O— to form a 5- to 8-membered ring together with the atoms of Ar² to which they are bonded;

R⁷ is a hydrogen atom, or C₁₋₃ alkyl group;

R⁷ and an atom of Ar² may be bonded via a single bond to form a 5- to 8-membered ring;

R⁸ is a hydrogen atom, a C₁₋₆ alkyl group, an adamantyl group, a C₁₋₆ cycloalkyl group, a cyanomethyl group, an oxetanyl group, a (C₁₋₃ alkylamino)carbonylmethyl group, a di(C₁₋₃ alkyl)aminocarbonylmethyl group, a (C₁₋₃ alkylamino)C₁₋₈ alkyl group, a di(C₁₋₃ alkyl)aminoC₁₋₈ alkyl group, a (hydroxy)C₁₋₈ alkyl group, a (carboxy)C₁₋₃ alkyl group, a (C₁₋₃ alkoxycarbonyl)C₁₋₃ alkyl group, or a (C₁₋₃ alkoxy)C₁₋₃ alkyl group;

R⁷ and R⁸ may be bonded each other via a single bond, —O—, —S(═O)_(m)—, or —NR⁴¹— to form a 3- to 8-membered ring, and further, the ring is optionally substituted with an amino group, an oxo group, or a C₁₋₃ alkyl group;

m represents an integer from 0 to 2;

R⁴¹ is a hydrogen atom or a C₁₋₃ alkyl group.]

[2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein X¹, X², and X³ are CH. [3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R¹ is a cyano group. [4] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R¹ is a fluorine atom. [5] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heteroaryl ring of Ar¹ is one of the following groups:

[6] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein L¹ is —O—. [7] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein L¹ is —CO—. [8] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein L¹ is —CH₂—. [9] The compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein R² is a methyl group. [10] The compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein R³ is a C₃₋₈ cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C₃₋₈ cycloalkyloxy group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkyl group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkoxy group optionally substituted with 1 to 6 R³¹, a di(C₁₋₄ alkyl)amino group optionally substituted with 1 to 6 R³¹, a (C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R³², an aryl group optionally substituted with 1 to 4 R³², or a heteroaryl group optionally substituted with 1 to 4 R³². [11] The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, wherein R³¹ is a halogen atom, a cyclopropylidene group, or a C₁₋₄ alkoxy group. [12] The compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof, wherein R³² is a halogen atom, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₁₋₃ alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group or a cyano group. [13] The compound according to any one of [1] to [12] or a pharmaceutically acceptable salt thereof, wherein the heteroaryl ring of Ar² is

[14] The compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof, wherein L² is a C₁₋₃ alkylene group optionally substituted with 1 to 2 R²¹. [15] The compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof, wherein L² is —CH₂—. [16] The compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof, wherein L² is —CH₂CH₂—. [17] The compound according to any one of [1] to [16] or a pharmaceutically acceptable salt thereof, wherein R⁷ is a hydrogen atom. [18] The compound according to any one of [1] to [17] or a pharmaceutically acceptable salt thereof, wherein R⁸ is a hydrogen atom. [19] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) is selected from the following (1) to (150):

-   (1)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile -   (2)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile -   (3)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile -   (4)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(5-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile -   (5)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(4-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile -   (6)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile -   (7)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (8)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(2-methylpropyl)pyrazol-3-yl]oxybenzonitrile -   (9)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile -   (10)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile -   (11)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (12)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile -   (13)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyridin-4-yl)oxybenzonitrile -   (14)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile -   (15)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile -   (16)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile -   (17)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyridin-4-yl)oxybenzonitrile -   (18)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile -   (19)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (20)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile -   (21)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile -   (22)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(6-phenylpyridazin-4-yl)oxybenzonitrile -   (23)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile -   (24)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (25)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile -   (26)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (27)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile -   (28)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2,5-dimethylpyrazol-3-yl)oxybenzonitrile -   (29)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile -   (30)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (31)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-butyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (32)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (33)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (34)     4-[5-(aminomethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (35)     4-[5-(aminomethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (36)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile -   (37)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile -   (38)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile -   (39)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile -   (40)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile -   (41)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile -   (42)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (43)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile -   (44)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile -   (45)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile -   (46)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopentyl-2-methylpyrazol-3-yl)oxybenzonitrile -   (47)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile -   (48)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile -   (49)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2S)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile -   (50)     4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxybenzonitrile -   (51)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2R)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile -   (52)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-4-yl]oxybenzonitrile -   (53)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile -   (54)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile -   (55)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl]oxybenzonitrile -   (56)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-[2-methoxyethyl(methyl)amino]-6-methylpyridin-4-yl]oxybenzonitrile -   (57)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(propan-2-ylamino)pyridin-4-yl]oxybenzonitrile -   (58)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile -   (59)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3S)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile -   (60)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile -   (61)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxybenzonitrile -   (62)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile -   (63)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile -   (64)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyrimidin-4-yl)oxybenzonitrile -   (65)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile -   (66)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile -   (67)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxybenzonitrile -   (68)     4-[5-(aminomethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile -   (69)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile -   (70)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile -   (71)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile -   (72)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile -   (73)     4-[5-(aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl]oxybenzonitrile -   (74)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile -   (75)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile -   (76)     4-[5-(aminomethyl)pyridin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)oxybenzonitrile -   (77)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(5-phenyl-1,3,4-thiadiazol-2-yl)oxy]benzonitrile -   (78)     4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile -   (79)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2-methylpropyl)amino]pyrazol-3-yl]oxybenzonitrile -   (80)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[cyclopropylmethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile -   (81)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propyl)amino]pyrazol-3-yl]oxybenzonitrile -   (82)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxybenzonitrile -   (83)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propan-2-yl)amino]pyrazol-3-yl]oxybenzonitrile -   (84)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile -   (85)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2,2,2-trifluoroethyl)amino]pyrazol-3-yl]oxybenzonitrile -   (86)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile -   (87)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile -   (88)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile -   (89)     4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile -   (90)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile -   (91)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile -   (92)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile -   (93)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile -   (94)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile -   (95)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile -   (96)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]oxybenzonitrile -   (97)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[ethyl(propan-2-yl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile -   (98)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(2-methylpropoxy)pyrimidin-4-yl]oxybenzonitrile -   (99)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(diethylamino)-2-methylpyrimidin-4-yl]oxybenzonitrile -   (100)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[methyl(propan-2-yl)amino]pyrimidin-4-yl]oxybenzonitrile -   (101)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile -   (102)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile -   (103)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,5-tetrafluoropyrrolidin-1-yl)pyrazol-3-yl]oxybenzonitrile -   (104)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile -   (105)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile -   (106)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazol-3-yl]oxybenzonitrile -   (107)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[I-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile -   (108)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile -   (109)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2,2-dimethylpropyl)-3-methylpyrazol-4-yl]oxybenzonitrile -   (110)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile -   (111)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-ethyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile -   (112)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)-3-(trifluoromethyl)pyrazol-4-yl]oxybenzonitrile -   (113)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methyl-1,3-thiazol-5-yl)pyrazol-3-yl]oxybenzonitrile -   (114)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(5-methyl-1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile -   (115)     2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine -   (116)     5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazole-3-amine -   (117)     2-[6-[4-fluoro-2-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine -   (118)     2-[2-[4-fluoro-2-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine -   (119)     2-[2-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine -   (120)     2-[6-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine -   (121)     5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazole-3-amine -   (122)     5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazole-3-amine -   (123)     5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazole-3-amine -   (124)     5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazole-3-amine -   (125)     5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazole-3-amine -   (126)     5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N,1-trimethylpyrazole-3-amine -   (127)     2-[6-[4-fluoro-2-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxyphenyl]pyridin-3-yl]ethanamine -   (128)     [2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methanamine -   (129)     2-[2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine -   (130)     2-[6-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine -   (131)     2-[6-[2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-fluorophenyl]pyridin-3-yl]ethanamine -   (132)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile -   (133)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile -   (134)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile -   (135)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile -   (136)     4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile -   (137)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile -   (138)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile -   (139)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile -   (140)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazole-4-carbonyl)benzonitrile -   (141)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile -   (142)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile -   (143)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile -   (144)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile -   (145)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile -   (146)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile -   (147)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile -   (148)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile -   (149)     4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile -   (150)     4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile.     [20] pharmaceutical composition comprising the compound according to     any one of [1] to [19] or a pharmaceutically acceptable salt     thereof.     [21] A pharmaceutical composition having TRPC6 channel inhibitory     activity, comprising the compound according to any one of [1] to     [19] or a pharmaceutically acceptable salt thereof.     [12] A therapeutic or prophylactic agent for nephrotic syndrome,     membranous nephropathy, acute renal failure, sepsis, chronic renal     failure, diabetic nephropathy, pulmonary hypertension, acute lung     injury, heart failure, malignant tumors, or muscular dystrophy,     comprising the compound according to any one of [1] to [19] or a     pharmaceutically acceptable salt thereof.

Advantageous Effects of Invention

The present invention provides a novel compound or a pharmaceutically acceptable salt thereof, having TRPC6 inhibitory activity, and a pharmaceutical composition and a therapeutic or prophylactic drug for the disease associated with TRPC6, including thereof.

DESCRIPTION OF EMBODIMENTS

Terms used alone or in combination in the present description will be explained below. Unless otherwise stated, the explanation of each substituent shall be common to each site. In addition, combinations of substituents and variables are permissible only if such combinations result in chemically stable compounds. When the substituent itself is substituted with two or more groups, these many groups can exist on the same or different carbon atom as long as a stable structure is formed.

In the present invention, the number situated to the right of carbon atom indicates the number of carbon atoms. For example, “C₁₋₆” represents having “1 to 6 carbon atoms.” For example, a “C₁₋₄ alkyl group” means an alkyl group having 1 to 4 carbon atoms. The number of carbon atoms in other groups is handled in the same manner. Incidentally, for example, in an expression such as “(C₁₋₃ alkyl)carbonyl group”, the number of carbon atoms of C₁₋₃ represents the number of carbon atoms of the C₁₋₃ alkyl in the parentheses, and the carbon in the carbonyl is not considered. The number of carbon atoms in a similar representation is calculated in the same manner. Unless otherwise specified, the method of naming a substituent shall be performed by naming from the terminal portion of the functional group and then naming the functional group adjacent to the binding point.

In the present invention, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present invention, “alkyl group” means a saturated linear or branched aliphatic hydrocarbon group and includes, for example, a methyl group, a ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a neopentyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group and the like.

In the present invention, the “cycloalkyl group” means a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like.

In the present invention, a “heterocycloalkyl group” means a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring in which one or more carbon atoms are substituted with a hetero atom selected from O, S and N, and includes, for example, an aziridino group, an azetidino group, an oxetanyl group, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an imidazolidinyl group, a pyrazoridinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.

In the present invention, the “alkoxy group”, “cycloalkyloxy group” and “heterocycloalkyloxy group” mean an oxy group substituted with an alkyl group, a cycloalkyl group or a heterocycloalkyl group.

In the present invention, “(alkoxy)alkoxy group” and “(carboxy)alkoxy group” mean an alkoxy group substituted with an alkoxy group or a carboxy group. For example, “(C₁₋₃ alkoxy)C₁₋₃ alkoxy group” means an alkoxy group having 1 to 3 carbon atoms substituted with an alkoxy group having 1 to 3 carbon atoms.

In the present invention, “(alkoxy)carbonyl group” means a carbonyl group substituted with an alkoxy group. For example, “(C₁₋₃ alkoxy)carbonyl group” means a carbonyl group substituted with an alkoxy group having 1 to 3 carbon atoms.

In the present invention, “(alkyl) amino group”, “(cycloalkyl) amino group” and “(heterocycloalkyl) amino group” mean an amino group substituted with one alkyl group, cycloalkyl group and heterocycloalkyl group, respectively. For example, “(C₃₋₈ heterocycloalkyl)amino group” means an amino group substituted with a 3- to 8-membered heterocycloalkyl group.

In the present invention, “di(alkyl)amino group” means an amino group substituted with two of the same or different alkyl groups. For example, “di(C₁₋₆ alkyl)amino group” means an amino group substituted with two of the same or different alkyl groups having 1 to 6 carbon atoms.

In the present invention, “(alkylcarbonyl)amino group” means an amino group substituted with one alkylcarbonyl group. For example, “(C₁₋₃ alkyl)carbonylamino group” means an amino group substituted with one (C₁₋₃ alkyl)carbonyl group.

In the present invention, “(alkylamino)carbonyl group” means a carbonyl group substituted with an alkylamino group. Similarly, “di(alkyl)aminocarbonyl group” means a carbonyl group substituted with a di(alkyl)amino group.

In the present invention, “alkoxyalkyl group”, “alkoxycarbonylalkyl group”, “di(alkyl)aminoalkyl group”, “hydroxyalkyl group” and “carboxyalkyl group” mean an alkyl group substituted with an alkoxy group, an alkoxycarbonyl group, a di(alkyl)amino group, a hydroxy group and a carboxy group, respectively. Further, “di(alkyl) aminocarbonylmethyl group” means a methyl group substituted with a di(alkyl)aminocarbonyl group.

In the present invention, “alkylene group” means a divalent group derived by removing one hydrogen atom at an arbitrary position from the “alkyl group”, and includes, for example, a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an isobutylene group, an n-pentylene group, an n-hexylene group and the like.

In the present invention, “cycloalkylene group” means a divalent group derived by removing one hydrogen atom at an arbitrary position from the “cycloalkyl group”, and includes, for example, a cyclopropylene group, a cyclobutylene group, a cyclohexylene group and the like.

In the present invention, “heterocycloalkylene group” means a divalent group derived by removing one hydrogen atom at an arbitrary position from the “heterocycloalkyl group”.

In the present invention, “optionally substituted C₁₋₃ alkyl group” represents an alkyl group having 1 to 3 carbon atoms which may have one or more substituents at substitutable positions. When a plurality of substituents is present, each substituent may be the same or different. Similar expressions have the same meaning.

In the present invention, “aryl group” means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms, and includes, for example, a phenyl group, a naphthyl group, an indenyl group, an azulenyl group and the like. “Aryl ring” refers to the ring portion of an aryl group.

In the present invention, “heteroaryl group” means a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic group having 1 to 5 heteroatoms selected from O, S, and N. Heteroaryl group includes a pyridyl group, a pyrazil group, a pyrimidyl group, a pyridadyl group, a furyl group, a thienyl group, an isooxazolyl group, an isothiazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiazolyl group, a benzoimidazolyl group, a benzoxazolyl group, a pyranyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazinyl group, a triazolyl group, a benzoxazolyl group, a benzoisoxazolyl group and the like. “Heteroaryl ring” refers to the ring portion of a heteroaryl group. “Nitrogen-containing heteroaryl ring” means a heteroaryl ring containing one or more Ns on the ring.

In the formula (I), X¹, X², and X³ are independently CH, N, or CY, and at least one of X¹, X², and X³ is CH or CY. Preferably, X¹, X², and X³ are CH.

Y is a halogen atom or a methyl group.

In the formula (I), R¹ is a cyano group, a fluorine atom, or a chlorine atom, and preferably a cyano group or a fluorine atom.

In the formula (I), linker L¹ is —O—, —S—, —SO—, —CH(R¹¹)—, —C(═CH₂)—, —CO—, a 1,1-cyclopropylidene group, or —NR¹²—, preferably, —O—, —S—, —CH(R¹¹)—, —CO—, or —NR¹²—, and more preferably —O—, —CO—, or —CH₂—.

R¹¹ is a hydrogen atom, a hydroxy group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, or a C₁₋₃ alkoxy group optionally substituted with 1 to 2 cyano groups.

R¹² is a hydrogen atom or a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms.

In the formula (I), Ar¹ is a nitrogen-containing heteroaryl ring optionally substituted with 1 to 3 R², and preferably has the following structures.

R² is independently a halogen atom, a cyano group, or a C₁₋₄ alkyl group optionally substituted with 1 to 3 halogen atoms, preferably a C₁₋₄ alkyl group optionally substituted with 1 to 3 halogen atoms, and more preferably a methyl group. When R² and R³ are bonded to atoms adjacent to each other on Ar¹, R² and R³ may be bonded via a single bond or —O— to form a 5- to 7-membered ring together with the atoms on Ar¹ to which they are bonded.

In the formula (I), R³ is a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, a (C₁₋₃ alkylcarbonyl)amino group, a (C₁₋₆ alkylamino)carbonyl group, a di(C₁₋₃ alkyl)aminocarbonyl group, a (C₁₋₃ alkoxy)carbonyl group, a (C₃₋₈ cycloalkyl)amino group, a (C₃₋₈ heterocycloalkyl)amino group, a C₃₋₈ cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C₃₋₈ cycloalkyloxy group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkyl group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkoxy group optionally substituted with 1 to 6 R³¹, a di(C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a (C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R³², an aryl group optionally substituted with 1 to 4 R³², or a heteroaryl group optionally substituted with 1 to 4 R³².

R³¹ is independently a halogen atom, a hydroxy group, a cyclopropylidene group, a C₃₋₈ cycloalkyl group optionally substituted with 1 to 3 halogen atoms, a 3- to 8-membered heterocycloalkyl group, an oxetanylidene group, a C₁₋₄ alkoxy group, or a 3- to 8-membered cycloalkyloxy group.

R³² is independently a halogen atom, a hydroxy group, an acetylamino group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₁₋₃ alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, a cyano group, a carboxy group, a (C₁₋₃ alkoxy)carbonyl group, a (C₁₋₃ alkyl)sulfonyl group, a carboxamide group, or a benzyloxy group.

In the formula (I), preferred R³ is a C₃₋₈ cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C₃₋₈ cycloalkyloxy group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkyl group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkoxy group optionally substituted with 1 to 6 R³¹, a di(C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a (C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R³², an aryl group optionally substituted with 1 to 4 R³² or a heteroaryl group optionally substituted with 1 to 4 R³².

Preferred R³¹ is a halogen atom, a cyclopropylidene group, or a C₁₋₄ alkoxy group.

Preferred R³² is a halogen atom, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₁₋₃ alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, or a cyano group.

In the formula (I), Ar² is an aryl ring optionally substituted with 1 to 4 R⁴, or a heteroaryl ring optionally substituted with 1 to 4 R⁴, preferably a heteroaryl ring optionally substituted with 1 to 4 R⁴, and more preferably a pyridine ring or a pyrimidine ring having a substitution pattern of the following structure.

R⁴ is independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C₁₋₃ alkyl)amino group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, or a C₁₋₃ alkoxy group.

In the formula (I), L² is a single bond, a C₁₋₆ alkylene group optionally substituted with 1 to 3 R²¹, a C₃₋₈ cycloalkylene group optionally substituted with 1 to 3 R²¹, or a 4- to 8-membered heterocycloalkylene group optionally substituted with 1 to 3 R²¹. L² may be bonded at any position to Ar² or —NR⁷R⁸ which is located at either end of it. One sp³ carbon atom at any position of L² may be replaced by a structure of —O— or —NR²²—. Preferred L² is a C₁₋₃ alkylene group optionally substituted with 1 to 2 R²¹, and more preferably —CH₂— or —CH₂CH₂—.

R²¹ is independently a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, a C₁₋₆ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₃₋₈ cycloalkyl group, a C₁₋₆ alkoxy group, a (C₁₋₃ alkoxy)C₁₋₃ alkyl group, a (C₁₋₃ alkoxy)C₁₋₃ alkoxy group, a (hydroxy) C₁₋₆ alkyl group, a (carboxy)C₁₋₃ alkyl group, a (carboxy)C₁₋₃ alkoxy group, a (C₁₋₃ alkoxy)carbonyl group, a (C₁₋₃ alkoxycarbonyl)C₁₋₃ alkyl group, a (C₁₋₆ alkylamino)carbonyl group, a di(C₁₋₃ alkyl) aminocarbonyl group, a phenyl group optionally substituted with 1 to 3 halogen atoms, a heteroaryl group optionally substituted with 1 to 3 halogen atoms, or a phenoxy group optionally substituted with 1 to 3 halogen atoms. Preferred R²¹ is a halogen atom, a hydroxy group, an oxo group, an oxetanylidene group, or a C₁₋₆ alkyl group optionally substituted with 1 to 3 halogen atoms, and more preferred is a halogen atom or a hydroxy group.

R²² is a hydrogen atom or a C₁₋₃ alkyl group.

L² and R⁷ may be bonded via a single bond, —O—, —S(═O)_(n)—, or —NR²³— to form a 4- to 8-membered ring containing a nitrogen atom to which L² and R⁷ are bonded, and the ring is optionally substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups, wherein n represents an integer from 0 to 2.

R²³ is a hydrogen atom or a C₁₋₃ alkyl group.

When L² and R are bonded to atoms adjacent to each other on Ar², they may be bonded via a single-bond or —O— to form a 5- to 8-membered ring together with the atoms of Ar² to which they are bonded.

In the formula (I), R⁷ is a hydrogen atom or a C₁₋₃ alkyl group, and more preferably a hydrogen atom. R⁷ and an atom of Ar² may be bonded via a single bond to form a 5- to 8-membered ring.

In the formula (I), R⁸ is a hydrogen atom, a C₁₋₆ alkyl group, an adamantyl group, a C₁₋₆ cycloalkyl group, a cyanomethyl group, an oxetanyl group, a (C₁₋₃ alkylamino)carbonylmethyl group, a di(C₁₋₃ alkyl)aminocarbonylmethyl group, a (C₁₋₃ alkylamino)C₁₋₈ alkyl group, a di(C₁₋₃ alkyl)aminoC₁₋₈ alkyl group, a (hydroxy)C₁₋₈ alkyl group, a (carboxy)C₁₋₃ alkyl group, a (C₁₋₃ alkoxycarbonyl)C₁₋₃ alkyl group, or a (C₁₋₃ alkoxy)C₁₋₃ alkyl group. More preferred R⁸ is a hydrogen atom.

R⁷ and R⁸ may be bonded each other via a single bond, —O—, —S(═O)_(m)—, or —NR⁴¹— to form a 3- to 8-membered ring, and further, the ring is optionally substituted with an amino group, an oxo group, or a C₁₋₃ alkyl group, wherein m represents an integer from 0 to 2.

R⁴¹ is a hydrogen atom or a C₁₋₃ alkyl group.

Among the compounds of the present invention, preferable is the following compound group, that is, the compound group in the formula (I),

wherein,

X¹, X², and X³ are CH,

R¹ is a cyano group or a fluorine atom,

linker L¹ is —O—, —CO—, or —CH₂—,

Ar¹ has the following structure,

R² is a methyl group,

R³ is a C₃₋₈ cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C₃₋₈ cycloalkyloxy group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkyl group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkoxy group optionally substituted with 1 to 6 R³¹, a di(C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a (C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R³², an aryl group optionally substituted with 1 to 4 R³² or a heteroaryl group optionally substituted with 1 to 4 R³².

R³¹ is a halogen atom, a cyclopropylidene group, or a C₁₋₄ alkoxy group, and

R³² is a halogen atom, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₁₋₃ alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, or a cyano group.

Ar² is a pyridine ring or a pyrimidine ring having a substitution pattern of the following structure.

L² is —CH₂— or —CH₂CH₂—,

R⁷ is a hydrogen atom, and

R⁸ is a hydrogen atom.

Specific examples of the compound of the formula (I) include the compounds shown in the following Table 1.

TABLE 1 Compound number Structural formula Compound name   1

4-[4-(aminomethyl)phenyl]-3-[(6- phenylpyrimidin-4- yl)amino]benzonitrile   2

4-[4-(2-aminoethyl)phenyl]-3-[(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)amino]benzonitrile   3

3-[(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)amino]-4-spiro[3H- 2-benzofuran-1,3′-azetidin]-5- ylbenzonitrile   4

4-[4-(2-aminoacetyl)phenyl]-3-[(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)amino]benzonitrile   5

3-[methyl-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)amino]-4-(1′- methylspiro[3H-2-benzofuran-1,3′- azetidin]-5-yl)benzonitrile   6

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [methyl-(2-methyl-5-phenylpyrazol- 3-yl)amino]benzonitrile   7

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile   8

4-[4-(2-aminoacetyl)phenyl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile   9

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  10

3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxy-4-[4-(4- methylpiperazin-1- yl)phenyl]benzonitrile  11

4-[4-(2-amino-1- methoxyethyl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  12

3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxy-4-(4-piperazin- 1-ylphenyl)benzonitrile  13

4-[4-(2-amino-1- phenoxyethyl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  14

4-(2-aminopyrimidin-5-yl)-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  15

4-[4-(2-aminoethyl)phenyl]-3-[6- (diethylamino)-2-methylpyrimidin-4- yl]oxybenzonitrile  16

4-[4-(2-aminoethyl)phenyl]-3-[6- (dipropylamino)-2-methylpyrimidin- 4-yl]oxybenzonitrile  17

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-6-piperidin-1-ylpyrimidin-4- yl)oxybenzonitrile  18

4-[4-(2-aminoethyl)phenyl]-3-[6-(4,4- difluoropiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  19

4-[4-(2-aminoethyl)phenyl]-3-[6-(3,3- difluoropiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  20

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(2-methylpyrazol-3- yl)pyrimidin-4-yl]oxybenzonitrile  21

4-[4-(2-aminoethyl)phenyl]-3-[6-(2- cyanophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  22

4-[4-(2-aminoethyl)phenyl]-3-[6-(2- hydroxyphenyl)-2-methylpyrimidin- 4-yl]oxybenzonitrile  23

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-[2- (trifluoromethyl)phenyl]pyrimidin-4- yl]oxybenzonitrile  24

4-[4-(2-aminoethyl)phenyl]-3-[6-(3,3- difluoroazetidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  25

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-6-pyrrolidin-1-ylpyrimidin-4- yl)oxybenzonitrile  26

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(3,3,4,4- tetrafluoropyrrolidin-1-yl)pyrimidin- 4-yl]oxybenzonitrile  27

4-[4-(2-aminoethyl)phenyl]-3-[6- (azepan-1-yl)-2-methylpyrimidin-4- yl]oxybenzonitrile  28

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(1-methylpyrrol-2- yl)pyrimidin-4-yl]oxybenzonitrile  29

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(1-methylpyrrol-3- yl)pyrimidin-4-yl]oxybenzonitrile  30

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(1,3-thiazol-4-yl)pyrimidin- 4-yl]oxybenzonitrile  31

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(1,4-oxazepan-4- yl)pyrimidin-4-yl]oxybenzonitrile  32

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-6-thiophen-3-ylpyrimidin-4- yl)oxybenzonitrile  33

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-6-thiophen-2-ylpyrimidin-4- yl)oxybenzonitrile  34

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(1,3-oxazol-2-yl)pyrimidin- 4-yl]oxybenzonitrile  35

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(2,2,2- trifluoroethoxy)pyrimidin-4- yl]oxybenzonitrile  36

4-[4-(2-aminoethyl)phenyl]-3-[6-(3- fluoropropoxy)-2-methylpyrimidin-4- yl]oxybenzonitrile  37

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(3,3,3- trifluoropropoxy)pyrimidin-4- yl]oxybenzonitrile  38

4-[4-(2-aminoethyl)phenyl]-3-(6- butoxy-2-methylpyrimidin-4- yl)oxybenzonitrile  39

4-[4-(2-aminoethyl)phenyl]-3-[6- (cyclohexylmethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  40

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(1,3-thiazol-2-yl)pyrimidin- 4-yl]oxybenzonitrile  41

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-(3-methylbutoxy)pyrimidin- 4-yl]oxybenzonitrile  42

4-[4-(2-aminoethyl)phenyl]-3-[6-(3,3- dimethylbutoxy)-2-methylpyrimidin- 4-yl]oxybenzonitrile  43

4-[4-(2-aminoethyl)phenyl]-3-[6- (cyclobutylmethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  44

4-[4-(2-aminoethyl)phenyl]-3-[6- (cyclopentylmethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  45

4-[4-(2-aminoethyl)phenyl]-3-(6- cyclopentyloxy-2-methylpyrimidin-4- yl)oxybenzonitrile  46

4-[4-(2-aminoethyl)phenyl]-3-(6- cyclopentyl-2-methylpyrimidin-4- yl)oxybenzonitrile  47

4-[4-(2-aminoethyl)phenyl]-3-[6-(2,2- dimethylpropoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  48

4-[4-(2-aminoethyl)phenyl]-3-[6-(2- methoxyethoxy)-2-methylpyrimidin- 4-yl]oxybenzonitrile  49

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-6-[(1- methylcyclopropyl)methoxy] pyrimidin-4-yl]oxybenzonitrile  50

4-[4-(2-aminoethyl)phenyl]-3-(6- morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  51

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(6- morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  52

4-[4-(azetidin-3-yl)phenyl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  53

3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxy-4-(4-pyrrolidin- 3-ylphenyl)benzonitrile  54

ethyl 3-[2-[4-[4-cyano-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]phenyl]ethylamino] propanoate  55

3-[3-[4-[4-cyano-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]phenyl]azetidin-1- yl]propanoic acid  56

3-[2-[4-[4-cyano-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]phenyl]ethylamino] propanoic acid  57

4-[4-[2-(3- methoxypropylamino)ethyl]phenyl]- 3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  58

4-[4-[2-(3- hydroxypropylamino)ethyl]phenyl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  59

4-[4-(2-amino-1-phenylethyl)phenyl]- 3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  60

4-[4-[2-amino-1-(4- fluorophenyl)ethyl]phenyl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  61

4-[4-[2-amino-1-(3- fluorophenyl)ethyl]phenyl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  62

4-[4-(1-aminopropan-2-yl)phenyl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  63

2-[2-amino-1-[4-[4-cyano-2-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxyphenyl]phenyl]ethoxy] acetic acid  64

4-[4-[2-amino-1-(2- methoxyethoxy)ethyl]phenyl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  65

4-[4-(2-aminoethyl)phenyl]-3-(6- pyrrolidin-1-ylpyridazin-4- yl)oxybenzonitrile  66

4-[4-(2-aminoethyl)phenyl]-3-(6- piperidin-1-ylpyridazin-4- yl)oxybenzonitrile  67

4-[4-[1- (aminomethyl)cyclopropyl]phenyl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  68

4-[4-(1-amino-2-hydroxypropan-2- yl)phenyl]-3-(2-methyl-6-morpholin- 4-ylpyrimidin-4-yl)oxybenzonitrile  69

4-[4-(2-aminoethyl)phenyl]-3-(6- phenylpyridazin-4-yl)oxybenzonitrile  70

4-[4-(2-aminoethyl)phenyl]-3-[6-(2- hydroxyphenyl)pyridazin-4- yl]oxybenzonitrile  71

4-[5-(2-amino-1-hydroxyethyl)-4- methyl-1,3-thiazol-2-yl]-3-(2-methyl- 6-phenylpyrimidin-4- yl)oxybenzonitrile  72

4-[4-(2-amino-1-thiophen-3- ylethyl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  73

4-[4-[2-amino-1-(furan-3- yl)ethyl]phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  74

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  75

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  76

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (6-chloropyridazin-4- yl)oxybenzonitrile  77

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  78

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)oxybenzonitrile  79

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (5-chloropyridazin-3- yl)oxybenzonitrile  80

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (5-morpholin-4-ylpyridazin-3- yl)oxybenzonitrile  81

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (5-piperidin-1-ylpyridazin-3- yl)oxybenzonitrile  82

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(6- phenylpyridazin-4-yl)oxybenzonitrile  83

4-[4-[1- (aminomethyl)cyclopropyl]phenyl]-3- (6-phenylpyridazin-4- yl)oxybenzonitrile  84

2-[5-[2-[4-(2-aminoethyl)phenyl]-5- cyanophenoxy]pyridazin-3-yl]-6- fluorobenzonitrile  85

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  86

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  87

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (6-chloropyridazin-4- yl)oxybenzonitrile  88

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-chloropyridazin-3- yl)oxybenzonitrile  89

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  90

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)oxybenzonitrile  91

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-morpholin-4-ylpyridazin-3- yl)oxybenzonitrile  92

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-piperidin-1-ylpyridazin-3- yl)oxybenzonitrile  93

4-[4-(2-aminoethyl)phenyl]-3-[6-(2- cyanophenyl)pyridazin-4- yl]oxybenzonitrile  94

2-[5-[2-[4-(2-aminoethyl)phenyl]-5- cyanophenoxy]pyridazin-3- yl]benzamide  95

3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxy-4-(1,2,3,4- tetrahydroisoquinolin-7- yl)benzonitrile  96

4-[4-[2-(dimethylamino)-1- hydroxyethyl]phenyl]-3-(2-methyl-6- phenylpyrimidin-4-yl)oxybenzonitrile  97

4-[4-(1-hydroxy-2-pyrrolidin-1- ylethyl)phenyl]-3-(2-methyl-6- phenylpyrimidin-4-yl)oxybenzonitrile  98

4-[5-[2-(dimethylamino)-1- hydroxyethyl]-4-methyl-1,3-thiazol- 2-yl]-3-(2-methyl-6-phenylpyrimidin- 4-yl)oxybenzonitrile  99

4-[4-[2-(dimethylamino)-1- hydroxyethyl]-1,5-dimethylimidazol- 2-yl]-3-(2-methyl-6-phenylpyrimidin- 4-yl)oxybenzonitrile  100

4-[4-(2-amino-1-ethoxyethyl)phenyl]- 3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  101

4-[4-(3-amino-1,1,1-trifluoropropan- 2-yl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  102

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (6-phenylpyridazin-4- yl)oxybenzonitrile  103

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (6-phenylpyridazin-4- yl)oxybenzonitrile  104

4-[4-[2-(dimethylamino)-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  105

4-[4-[2-(dimethylamino)-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  106

4-[4-[2-(dimethylamino)-1- hydroxyethyl]phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  107

4-[4-(2-aminoethyl)phenyl]-3-(6- cyclopentyloxypyridazin-4- yl)oxybenzonitrile  108

4-[4-(2-aminoethyl)phenyl]-3-[6-(2,2- dimethylpropoxy)pyridazin-4- yl]oxybenzonitrile  109

4-[4-(2-aminoethyl)phenyl]-3-[6- (2,2,2-trifluoroethoxy)pyridazin-4- yl]oxybenzonitrile  110

4-[4-(2-aminoethyl)phenyl]-3-[6-(3,5- dimethyl-1,2-oxazol-4-yl)pyridazin-4- yl]oxybenzonitrile  111

4-[4-(2-aminoethyl)phenyl]-3-[6-[2- methyl-5-(trifluoromethyl)pyrazol-3- yl]pyridazin-4-yl]oxybenzonitrile  112

(2S)-1-[6-[2-[4-(2- aminoethyl)phenyl]-5- cyanophenoxy]-2-methylpyrimidin-4 yl]pyrrolidine-2-carbonitrile  113

4-[4-(2-aminoethyl)phenyl]-3-[6- morpholin-4-yl-2- (trifluoromethyl)pyrimidin-4- yl]oxybenzonitrile  114

4-[4-(2-aminoethyl)phenyl]-3-(6- pyridin-2-ylpyridazin-4- yl)oxybenzonitrile  115

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  116

4-[4-(2-aminoethyl)phenyl]-3-[6-(2- fluorophenyl)pyridazin-4- yl]oxybenzonitrile  117

4-[4-(2-aminoethyl)phenyl]-3-[6-[2- (trifluoromethoxy)phenyl]pyridazin- 4-yl]oxybenzonitrile  118

4-[4-(2-aminoethyl)phenyl]-3-[6-(2- methoxypheny)pyridazin-4- yl]oxybenzonitrile  119

N-[2-[5-[2-[4-(2-aminoethyl)phenyl]- 5-cyanophenoxy]pyridazin-3- yl]phenyl]acetamide  120

methyl 2-[5-[2-[4-(2- aminoethyl)phenyl]-5- cyanophenoxy]pyridazin-3- yl]benzoate  121

2-[5-[2-[4-(2-aminoethyl)phenyl]-5- cyanophenoxy]pyridazin-3-yl]benzoic acid  122

4-[4-(3-amino-1,1,1-trifluoropropan- 2-yl)phenyl]-3-(6-morpholin-4- ylpyridazin-4-yl)oxybenzonitrile  123

4-[4-(2-aminoethyl)phenyl]-3-[6- [(1S,2R)-2- hydroxycyclopentyl]oxypyridazin-4- yl]oxybenzonitrile  124

4-[4-(2-aminoethyl)phenyl]-3[6- [(1S,2S)-2- hydroxycyclopentyl]oxypyridazin-4- yl]oxybenzonitrile  125

4-[4-(2-aminoethyl)phenyl]-3-[6- (oxolan-3-yloxy)pyridazin-4- yl]oxybenzonitrile  126

4-[4-(2-aminoethyl)phenyl]-3-[6-(3,3- dimethylbutoxy)pyridazin-4- yl]oxybenzonitrile  127

4-[4-(2-aminoethyl)phenyl]-3-[6-[2- [(2-methylpropan-2- yl)oxy]ethoxy]pyridazin-4- yl]oxybenzonitrile  128

4-[4-(2-aminoethyl)phenyl]-3-(6- methyl-4-morpholin-4-ylpyridin-2- yl)oxybenzonitrile  129

4-[5-(2-amino-1-hydroxyethyl)-4- methyl-1,3-thiazol-2-yl]-3-(2-methyl- 6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  130

(2R)-1-[6-[2-[4-(2- aminoethyl)phenyl]-5- cyanophenoxy]-2-methylpyrimidin-4- yl]pyrrolidine-2-carbonitrile  131

4-(2-amino-1-oxo-2,3-dihydroinden- 5-yl)-3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  132

4-(1-amino-2,3-dihydro-1H-inden-5- yl)-3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  133

4-[4-(3-amino-1,1-difluoropropan-2- yl)phenyl]-3-(2-methyl-6-morpholin- 4-ylpyrimidin-4-yl)oxybenzonitrile  134

4-(2-amino-1-hydroxy-2,3-dihydro- 1H-inden-5-yl)-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  135

4-[3-(aminomethyl)pyrazol-1-yl]-3- (6-phenylpyridazin-4- yl)oxybenzonitrile  136

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  137

4-[4-(2-aminoethyl)phenyl]-3-(6- cyclopentylpyridazin-4- yl)oxybenzonitrile  138

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  139

4-[4-(3-amino-1,1-difluoropropan-2- yl)phenyl]-3-(6-morpholin-4 ylpyridazin-4-yl)oxybenzonitrile  140

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[6-(4- fluorophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  141

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[6-(3- fluorophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  142

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[2- methyl-6-(4-methylphenyl)pyrimidin- 4-yl]oxybenzonitrile  143

4-[5-[(dimethylamino)methyl]-4- methyl-1,3-thiazol-2-yl]-3-(2-methyl- 6-phenylpyrimidin-4- yl)oxybenzonitrile  144

4-[3-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  145

4-[4-(2-aminoethyl)phenyl]-3-(5- morpholin-4-ylpyridazin-3- yl)oxybenzonitrile  146

4-[4-(2-aminoacetyl)pyrazol-1-yl]-3- (2-methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  147

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [6-morpholin-4-yl-2- (trifluoromethyl)pyrimidin-4- yl]oxybenzonitrile  148

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [6-morpholin-4-yl-2- (trifluoromethyl)pyrimidin-4- yl]oxybenzonitrile  149

4-[4-(2-amino-1-hydroxyethyl)-3- fluorophenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  150

4-[4-(2-amino-1-hydroxyethyl)-3- chlorophenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  151

4-[4-(2-amino-1-hydroxyethyl)-3- (trifluoromethyl)phenyl]-3-(2-methyl- 6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  152

4-[4-(2-amino-1-hydroxyethyl)-3- hydroxyphenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  153

4-[4-(2-amino-1-hydroxyethyl)-2,3- difluorophenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  154

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-(6- phenylpyridazin-4-yl)oxybenzonitrile  155

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[6- morpholin-4-yl-2- (trifluoromethyl)pyrimidin-4- yl]oxybenzonitrile  156

4-[4-(2-amino-1-hydroxyethyl)-3- methoxyphenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  157

4-[4-(2-amino-1-hydroxyethyl)-2- methylphenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  158

4-[4-(2-amino-1-hydroxyethyl)-3- (cyanomethyl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  159

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[6-(3- chlorophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  160

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  161

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  162

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  163

4-[4-(2-aminoethyl)phenyl]-3-(2- methyl-5-pyridin-3-ylpyrazol-3- yl)oxybenzonitrile  164

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-5-(5-methylpyridin-2- yl)pyrazol-3-yl]oxybenzonitrile  165

4-[4-(2-aminoethyl)phenyl]-3-[5-(4- fluorophenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  166

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-6-pyridin-2-ylpyrimidin-4- yl)oxybenzonitrile  167

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [6-(3-fluorophenyl)-2- methylpyrimidin-4-yl]oxybenzonitrile  168

4-[2-(2-amino-1-hydroxyethyl)-1,3- thiazol-4-yl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  169

4-[4-(2-amino-1- hydroxyethyl)imidazol-1-yl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  170

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  171

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  172

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  173

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  174

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  175

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  176

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  177

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(2-methyl-5- pyridin-3-ylpyrazol-3- yl)oxybenzonitrile  178

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-5-pyridin-3-ylpyrazol-3- yl)oxybenzonitrile  179

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-pyridin-3-ylpyrazol-3- yl)oxybenzonitrile  180

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-[2-methyl-5- (5-methylpyridin-2-yl)pyrazol-3- yl]oxybenzonitrile  181

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [2-methyl-5-(5-methylpyridin-2- yl)pyrazol-3-yl]oxybenzonitrile  182

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(5-methylpyridin-2- yl)pyrazol-3-yl]oxybenzonitrile  183

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-[5-(4- fluorophenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  184

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [5-(4-fluorophenyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  185

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [5-(4-fluorophenyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  186

4-[4-(2-aminoethyl)phenyl]-3-[5-(3- fluorophenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  187

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [5-(3-fluorophenyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  188

4-[6-(2-aminoethyl)pyridin-3-yl]-3- (2-methyl-6-pyridin-3-ylpyrimidin-4- yl)oxybenzonitrile  189

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [2-methyl-6-(5-methylpyridin-2- yl)pyrimidin-4-yl]oxybenzonitrile  190

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [6-(4-fluorophenyl)-2- methylpyrimidin-4-yl]oxybenzonitrile  191

4-(7-amino-8-hydroxy-5,6,7,8- tetrahydronaphthalen-2-yl)-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  192

4-(5-amino-4-hydroxy-4,5,6,7- tetrahydroindazol-1-yl)-3-(2-methyl- 6-phenylpyrimidin-4- yl)oxybenzonitrile  193

4-(5-amino-4-hydroxy-4,5,6,7- tetrahydroindazol-2-yl)-3-(2-methyl- 6-phenylpyrimidin-4- yl)oxybenzonitrile  194

4-[3-(2-aminoethyl)phenyl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  195

4-[2-(2-amino-1-hydroxyethyl)-1,3- thiazol-4-yl]-3-(2-methyl-6- phenylpyrimidin-4-yl)oxybenzonitrile  196

4-[3-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[6-(1H- pyrrol-2-yl)pyridazin-4- yl]oxybenzonitrile  197

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile  198

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-[5-(3- fluorophenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  199

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [5-(3-fluorophenyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  200

4-[4-(2-amino-1- hydroxyethyl)imidazol-1-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  201

4-[4-(2-aminoacetyl)phenyl]-3-(2- methyl-6-phenylpyridin-4- yl)oxybenzonitrile  202

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  203

4-[3-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-(2- methyl-6-phenylpyridin-4- yl)oxybenzonitrile  204

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  205

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-(3-methylphenyl)pyrimidin- 4-yl]oxybenzonitrile  206

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-(3-methylphenyl)pyrimidin- 4-yl]oxybenzonitrile  207

3-(2-methyl-5-phenylpyrazol-3- yl)oxy-4-[5-[2-(oxetan-3 ylamino)ethyl]pyridin-2- yl]benzonitrile  208

3-(6-cyclopentyl-2-methylpyrimidin- 4-yl)oxy-4-[4-(2-oxopiperazin-1- yl)pyrazol-1-yl]benzonitrile  209

3-(6-cyclopentyl-2-methylpyrimidin- 4-yl)oxy-4-[4-(2-oxo-1,4-diazepan-1- yl)pyrazol-1-yl]benzonitrile  210

3-(6-cyclopentyl-2-methylpyrimidin- 4-yl)oxy-4-[4-(7-oxo-1,4-diazepan-1- yl)pyrazol-1-yl]benzonitrile  211

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-5-(2-methylpropyl)pyrazol-3- yl]oxybenzonitrile  212

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-[2-methyl-5 (2-methylpropyl)pyrazol-3- yl]oxybenzonitrile  213

4-[4-(2-aminoethyl)phenyl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  214

4-[4-(2-aminoacetyl)phenyl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  215

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  216

4-[4-(2-amino-1-hydroxyethyl)-1,3- thiazol-2-yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  217

3-(2-methyl-5-phenylpyrazol-3- yl)oxy-4-[4-(2-oxopiperazin-1- yl)pyrazol-1-yl]benzonitrile  218

3-(2-methyl-5-phenylpyrazol-3- yl)oxy-4-[4-(2-oxo-1,4-diazepan-1- yl)pyrazol-1-yl]benzonitrile  219

3-(2-methyl-5-phenylpyrazol-3- yl)oxy-4-[4-(7-oxo-1,4-diazepan-1- yl)pyrazol-1-yl]benzonitrile  220

3-[2-methyl-5- (trifluoromethyl)pyrazol-3-yl]oxy-4- [4-(2-oxopiperazin-1-yl)pyrazol-1- yl]benzonitrile  221

3-(6-cyclopentyl-2-methylpyrimidin- 4-yl)oxy-4-[4-(1,2,3,6- tetrahydropyridin-4-yl)pyrazol-1- yl]benzonitrile  222

4-[4-[(1S)-2-amino-1-hydroxyethyl]- 1,3-thiazol-2-yl]-3-(2-methyl-6- phenylpyrimidin-4-yl)oxybenzonitrile  223

4-[4-[(1R)-2-amino-1-hydroxyethyl]- 1,3-thiazol-2-yl]-3-(2-methyl-6- phenylpyrimidin-4-yl)oxybenzonitrile  224

4-[5-(2-amino-1-hydroxyethyl)-1,3- thiazol-2-yl]-3-(2-methyl-6- phenylpyrimidin-4-yl)oxybenzonitrile  225

4-[5-(2-amino-1-hydroxyethyl)-1,3- thiazol-2-yl]-3-(2-methyl-5- phenylpyrazol-3-yl)oxybenzonitrile  226

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-(2- methyl-6-phenylpyridin-4- yl)oxybenzonitrile  227

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile  228

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(2-methylpropyl)pyrazol- 3-yl]oxybenzonitrile  229

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-propan-2-ylpyrazol-3- yl)oxybenzonitrile  230

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-propylpyrazol-3- yl)oxybenzonitrile  231

4-[4-[(1R)-1-hydroxy-2- (methylamino)ethyl]pyrazol-1-yl]-3- (2-methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  232

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-pyrrolidin-1-ylpyrimidin-4- yl)oxybenzonitrile  233

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-piperidin-1-ylpyrimidin-4- yl)oxybenzonitrile  234

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-(4-propan-2-ylpiperidin-1- yl)pyrimidin-4-yl]oxybenzonitrile  235

4-[4-[(1R)-2-amino-1 hydroxyethyl]pyrazol-1-yl]-3-[6-(3,3- dimethylpiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  236

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(3,3- difluoroazetidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  237

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  238

4-[5-(2-amino-1-hydroxyethyl)-1,3- thiazol-2-yl]-3-(5-cyclobutyl-2- methylpyrazol-3-yl)oxybenzonitrile  239

3-(2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxy-4-(1-piperidin- 4-ylpyrazol-4-yl)benzonitrile  240

(2S)-2-amino-3-[4-[4-cyano-2-(2- methyl-6-phenylpyrimidin-4- yl)oxyphenyl]phenyl]propanamide  241

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  242

4-[4-(2-aminoethyl)phenyl]-3-[5- (methoxymethyl)-2,4- dimethylpyrazol-3-yl]oxybenzonitrile  243

4-[4-(2-aminoethyl)phenyl]-3-[2- methyl-5-(2-methylpropyl)-4-propan- 2-ylpyrazol-3-yl]oxybenzonitrile  244

4-[4-[(1R)-1-hydroxy-2-(oxetan-3- ylamino)ethyl]pyrazol-1-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  245

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [5-(cyclopentyloxymethyl)-2- methylpyrazol-3-yl]oxybenzonitrile  246

4-[5-(2-amino-1-hydroxyethyl)-1,3- thiazol-2-yl]-3-(6-phenylpyridazin-4- yl)oxybenzonitrile  247

4-[4-(2-amino-2- methylpropyl)phenyl]-3-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  248

4-[5-(2-amino-1- hydroxyethyl)pyrimidin-2-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  249

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  250

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  251

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(4- methoxypiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  252

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(3,3- difluoropyrrolidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  253

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-[4- (trifluoromethyl)piperidin-1- yl]pyrimidin-4-yl]oxybenzonitrile  254

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyridin-4- yl)oxybenzonitrile  255

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(propan-2- yloxymethyl)pyrazol-3- yl]oxybenzonitrile  256

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(4,4- difluoropiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  257

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(3,3- difluoropiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  258

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-pyridin-2-ylpyridin-4- yl)oxybenzonitrile  259

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  260

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-propylpyrazol-3- yl)oxybenzonitrile  261

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-propan-2-ylpyrazol-3- yl)oxybenzonitrile  262

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyridin-4- yl)oxybenzonitrile  263

4-[2-(2-amino-1-hydroxyethyl)-1,3- thiazol-5-yl]-3-(2-methyl-6- phenylpyrimidin-4-yl)oxybenzonitrile  264

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(trifluoromethyl)pyrazol- 3-yl]oxybenzonitrile  265

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(6- cyclopentyloxy-2-methylpyrimidin-4- yl)oxybenzonitrile  266

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(6- cyclohexyloxy-2-methylpyrimidin-4- yl)oxybenzonitrile  267

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-(2- methylpropoxy)pyrimidin-4- yl]oxybenzonitrile  268

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-(2,2,2- trifluoroethoxy)pyrimidin-4- yl]oxybenzonitrile  269

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(6- cyclobutyloxy-2-methylpyrimidin-4- yl)oxybenzonitrile  270

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6- (cyclobutylmethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  271

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6- [(2,2-difluorocyclopropyl)methoxy]- 2-methylpyrimidin-4- yl]oxybenzonitrile  272

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  273

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile  274

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  275

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  276

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-(5- cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  277

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-phenylpyridazin-4- yl)oxybenzonitrile  278

4-[5-(2-amino-1- hydroxyethyl)pyrimidin-2-yl]-3-(5- cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  279

4-[4-[(1R)-2-(cyanomethylamino)-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  280

4-[5-[2-(cyanomethylamino)-1- hydroxyethyl]pyridin-2-yl]-3-(5- cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  281

4-[5-[2-(cyanomethylamino)-1- hydroxyethyl]pyrimidin-2-yl]-3-(5- cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  282

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  283

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)oxybenzonitrile  284

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)oxybenzonitrile  285

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  286

4-[5-[2- (cyanomethylamino)ethyl]pyridin-2- yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  287

4-[5-(2-amino-1- hydroxyethyl)pyrazin-2-yl]-3-(5- cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  288

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-ethyl-2-methylpyrazol-3- yl)oxybenzonitrile  289

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  290

4-[5-(aminomethyl)pyrazin-2-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  291

3-(2-methyl-5-phenylpyrazol-3- yl)oxy-4-(5,6,7,8-tetrahydro-2,7- naphthylidin-3-yl)benzonitrile  292

3-(2-methyl-5-phenylpyrazol-3- yl)oxy-4-(5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2- yl)benzonitrile  293

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-ethyl-2-methylpyrazol-3- yl)oxybenzonitrile  294

4-[5-(2-amino-1,1- difluoroethyl)pyridin-2-yl]-3-(5- cyclobutyl-2-methylpyrazol-3- yl)oxybenzonitrile  295

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(2-cyanophenyl)-2- methylpyrimidin-4-yl]oxybenzonitrile  296

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(3,3-difluoroazetidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  297

4-[4-(2-amino-2- methylpropyl)phenyl]-3-(6- morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  298

4-[4-(aminomethyl)pyrazol-1-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  299

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2,5-dimethylpyrazol-3- yl)oxybenzonitrile  300

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methylpyrazol-3- yl)oxybenzonitrile  301

4-[5-(2-amino-1-hydroxy-2- methylpropyl)pyridin-2-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  302

4-[4-(2-amino-1-hydroxy-2- methylpropyl)pyrazol-1-yl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  303

4-[5-(2-amino-1-hydroxy-2- methylpropyl)pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  304

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (2,5-dimethylpyrazol-3- yl)oxybenzonitrile  305

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2,5-dimethylpyrazol-3- yl)oxybenzonitrile  306

4-[4-(2-aminoethyl)phenyl]-3-[(3- phenyl-1,2-oxazol-5- yl)oxy]benzonitrile  307

4-[5-(2-amino-1,1- difluoroethyl)pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  308

4-[5-(2-amino-1,1- difluoroethyl)pyridin-2-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  309

ethyl 5-[2-[5-(2-aminoethyl)pyridin- 2-yl]-5-cyanophenoxy]-1- methylpyrazole-3-carboxylate  310

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  311

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methylpyrazol-3- yl)oxybenzonitrile  312

4-[6-(2-aminoethyl)pyridazin-3-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  313

4-[5-(2-aminoethyl)pyrazin-2-yl]-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  314

4-[5-(2-amino-1- hydroxyethyl)pyrazin-2-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  315

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-cyclopropyl-6-methylpyridin-4- yl)oxybenzonitrile  316

5-[2-[5-(2-aminoethyl)pyridin-2-yl]- 5-cyanophenoxy]-1-methylpyrazole- 3-carboxylic acid  317

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  318

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-(5- butyl-2-methylpyrazol-3- yl)oxybenzonitrile  319

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-butyl-2-methylpyrazol-3- yl)oxybenzonitrile  320

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-[5-(2- methoxyphenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  321

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-[5-(2- hydroxyphenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  322

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-[2- methyl-5-(2- phenylmethoxyphenyl)pyrazol-3- yl]oxybenzonitrile  323

4-[5-(aminomethyl)pyridin-2-yl]-3- (2,5-dimethylpyrazol-3- yl)oxybenzonitrile  324

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-ethyl-2-methylpyrazol-3- yl)oxybenzonitrile  325

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  326

4-[5-(aminomethyl)pyridin-2-yl]-3- (5-ethyl-2-methylpyrazol-3- yl)oxybenzonitrile  327

4-[5-(aminomethyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  328

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  329

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  330

4-[6-(aminomethyl)pyridin-3-yl]-3- (5-ethyl-2-methylpyrazol-3- yl)oxybenzonitrile  331

4-[6-(aminomethyl)pyridin-3-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  332

4-[5-(aminomethyl)pyrazin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  333

4-[5-(2-amino-2- methylpropyl)pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  334

4-[5-(2-amino-2- methylpropyl)pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  335

4-[5-(2-amino-1-hydroxy-2- methylpropyl)pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  336

4-[5-(2-amino-1-hydroxy-2- methylpropyl)pyridin-2-yl]-3-(5- butyl-2-methylpyrazol-3- yl)oxybenzonitrile  337

4-[5-(2-amino-1- hydroxyethyl)pyrimidin-2-yl]-3-(5- butyl-2-methylpyrazol-3- yl)oxybenzonitrile  338

4-[5-(2-amino-2- methylpropyl)pyridin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  339

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(2- fluorophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  340

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(2- chlorophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  341

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(2- cyanophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  342

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(2- fluorophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  343

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(2- chlorophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  344

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[6-(2- cyanophenyl)-2-methylpyrimidin-4- yl]oxybenzonitrile  345

4-[5-(2-aminoethoxy)pyridin-2-yl]-3- (5-ethyl-2-methylpyrazol-3- yl)oxybenzonitrile  346

4-[2-(2-aminoethyl)pyrimidin-5-yl]-3 (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  347

4-[2-(2-aminoethyl)pyrimidin-5-yl]-3- (5-cyclopropyl-2-methylpyrazol-3 yl)oxybenzonitrile  348

4-[5-(2-aminoethoxy)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  349

4-[5-(2-aminoethoxy)pyridin-2-yl]-3- (2,5-dimethylpyrazol-3- yl)oxybenzonitrile  350

4-[5-(2-aminoethoxy)pyridin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  351

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-[2- (trifluoromethyl)phenyl]pyrimidin-4- yl]oxybenzonitrile  352

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-pyridin-2-ylpyrimidin-4- yl)oxybenzonitrile  353

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-[3- (trifluoromethyl)phenyl]pyrimidin-4- yl]oxybenzonitrile  354

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-(2-methylphenyl)pyrimidin- 4-yl]oxybenzonitrile  355

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-[2- (trifluoromethyl)phenyl]pyrimidin-4- yl]oxybenzonitrile  356

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-(2- methyl-6-pyridin-2-ylpyrimidin-4- yl)oxybenzonitrile  357

4-[4-[(1S)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-[3- (trifluoromethyl)phenyl]pyrimidin-4- yl]oxybenzonitrile  358

4-[4-[(1R)-2-amino-1- hydroxyethyl]pyrazol-1-yl]-3-[2- methyl-6-(2-methylphenyl)pyrimidin- 4-yl]oxybenzonitrile  359

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-cyclopropyl-4-fluoro-2- methylpyrazol-3-yl)oxybenzonitrile  360

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (4-fluoro-2-methyl-5-phenylpyrazol- 3-yl)oxybenzonitrile  361

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-propylpyrazol-3- yl)oxybenzonitrile  362

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-propan-2-ylpyrazol-3- yl)oxybenzonitrile  363

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-propylpyrazol-3- yl)oxybenzonitrile  364

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-propan-2-ylpyrazol-3- yl)oxybenzonitrile  365

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  366

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  367

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-tert-butyl-2-methylpyrazol-3- yl)oxybenzonitrile  368

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-(2-tert- butyl-5-cyclopropylpyrazol-3- yl)oxybenzonitrile  369

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-tert-butyl-5-cyclopropylpyrazol-3- yl)oxybenzonitrile  370

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-[5- cyclopropyl-2-(2,2,2- trifluoroethyl)pyrazol-3- yl]oxybenzonitrile  371

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyridin-2-ylpyridin-4- yl)oxybenzonitrile  372

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  373

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(5 cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  374

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  375

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  376

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1,1,2,2,2- pentafluoroethyl)pyrazol-3- yl]oxybenzonitrile  377

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[5-(4- chlorophenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  378

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-5-(2-methylphenyl)pyrazol-3- yl]oxybenzonitrile  379

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-cyclopropyl-2-(2,2,2- trifluoroethyl)pyrazol-3- yl]oxybenzonitrile  380

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-cyclopropyl-2-propan-2-ylpyrazol- 3-yl)oxybenzonitrile  381

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-phenyl-2-propan-2-ylpyrazol-3- yl)oxybenzonitrile  382

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- cyclopropyl-2-propan-2-ylpyrazol-3- yl)oxybenzonitrile  383

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- phenyl-2-propan-2-ylpyrazol-3- yl)oxybenzonitrile  384

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-(difluoromethyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  385

4-[5-(2-aminoethoxy)pyrimidin-2-yl]- 3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  386

4-[5-(2-aminoethoxy)pyrimidin-2-yl]- 3-(5-ethyl-2-methylpyrazol-3- yl)oxybenzonitrile  387

4-[5-(2-aminoethoxy)pyrimidin-2-yl]- 3-(2-methyl-6-morpholin-4-ylpyridin- 4-yl)oxybenzonitrile  388

4-[5-(2-aminoethyl)pyrazin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  389

4-[5-(2-aminoethyl)pyrazin-2-yl]-3- [2-methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile  390

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(1,3-thiazol-2-yl)pyrazol- 3-yl]oxybenzonitrile  391

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1,3-thiazol-2-yl)pyrazol- 3-yl]oxybenzonitrile  392

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- cyclopentyl-2-methylpyrazol-3- yl)oxybenzonitrile  393

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-cyclopentyl-2-methylpyrazol-3- yl)oxybenzonitrile  394

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  395

4-[5-(2-aminopropan-2-yl)pyridin-2- yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile  396

4-[5-(1-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  397

4-[5-(2-aminopropan-2-yl)pyridin-2- yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  398

4-[5-(1-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  399

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- ethoxy-2-methylpyrazol-3- yl)oxybenzonitrile  400

4-[5-(2-aminopropan-2-yl)pyridin-2- yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  401

4-[5-(1-aminoethyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  402

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-(3-fluorophenyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  403

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[5-(3- fluorophenyl)-2-methylpyrazol-3- yl]oxybenzonitrile  404

4-[5-(2-amino-1- hydroxyethyl)pyrimidin-2-yl]-3-[5-(3- fluorophenyl)-2-methylpyrazol-3 yl]oxybenzonitrile  405

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5-tert- butyl-2-methylpyrazol-3- yl)oxybenzonitrile  406

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(5- tert-butyl-2-methylpyrazol-3- yl)oxybenzonitrile  407

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- cyclopropyl-2-propan-2-ylpyrazol-3- yl)oxybenzonitrile  408

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(5- cyclopropyl-2-propan-2-ylpyrazol-3- yl)oxybenzonitrile  409

methyl 2-amino-2-[6-[4-cyano-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]acetate  410

2-amino-2-[6-[4-cyano-2-(2-methyl- 6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]acetic acid  411

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[5- cyclopropyl-2-(2,2,2- trifluoroethyl)pyrazol-3- yl]oxybenzonitrile  412

4-[5-(1-amino-2- hydroxyethyl)pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  413

4-[5-(1-amino-2- hydroxyethyl)pyridin-2-yl]-3-(5-tert- butyl-2-methylpyrazol-3- yl)oxybenzonitrile  414

4-(3-amino-1,2-benzoxazol-6-yl)-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  415

4-(3-amino-1,2-benzoxazol-6-yl)-3- (2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  416

4-(5-aminopyridin-2-yl)-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  417

4-(5-aminopyrimidin-2-yl)-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  418

2-amino-2-[6-[4-cyano-2-(2-methyl- 6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]acetamide  419

3-(2-methyl-6-morpholin-4-ylpyridin- 4-yl)oxy-4-[5-(2-morpholin-4- ylethyl)pyrimidin-2-yl]benzonitrile  420

4-[5-(1-amino-2- hydroxyethyl)pyrimidin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  421

4-[5-(1-amino-2- hydroxyethyl)pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  422

4-[5-[amino(cyano)methyl]pyridin-2- yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  423

4-[5-[amino(cyano)methyl]pyridin-2- yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  424

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[5-(morpholin-4- ylmethyl)pyridin-2-yl]benzonitrile  425

3-(2-methyl-6-morpholin-4-ylpyridin- 4-yl)oxy-4-[5-(morpholin-4- ylmethyl)pyridin-2-yl]benzonitrile  426

2-amino-2-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]acetic acid  427

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-(5-morpholin-2-ylpyridin-2- yl)benzonitrile  428

2-amino-2-[6-[4-cyano-2-(2-methyl- 5-phenylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]acetic acid  429

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  430

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  431

4-[2-(2-aminoethylamino)pyrimidin- 5-yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  432

4-[5-(2-aminoethylamino)pyrimidin- 2-yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  433

2-amino-2-[6-[4-cyano-2-(6- phenylpyridazin-4- yl)oxyphenyl]pyridin-3-yl]acetic acid  434

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  435

(2S)-2-amino-3-[4-[4-cyano-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]phenyl]propanoic acid  436

(2S)-2-amino-3-[4-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]phenyl]propanoic acid  437

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2,6- dimethylpyridin-4-yl)oxybenzonitrile  438

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2,6-dimethylpyridin-4- yl)oxybenzonitrile  439

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-[(2S)-2- (difluoromethyl)morpholin-4-yl]-6- methylpyridin-4-yl]oxybenzonitrile  440

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile  441

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile  442

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile  443

4-[4-(aminomethyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  444

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-[(2R)-2- (difluoromethyl)morpholin-4-yl]-6- methylpyridin-4-yl]oxybenzonitrile  445

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)pyridin- 4-yl]oxybenzonitrile  446

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)pyridin- 4-yl]oxybenzonitrile  447

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-piperidin-1-ylpyrimidin- 4-yl)oxybenzonitrile  448

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyrimidin- 4-yl)oxybenzonitrile  449

2-amino-3-[1-[4-cyano-2-(2-methyl- 6-phenylpyrimidin-4- yl)oxyphenyl]indol-3-yl]propanoic acid  450

4-(4-aminopyridin-2-yl)-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  451

4-(6-aminopyridin-2-yl)-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  452

4-(1-aminoisoquinolin-7-yl)-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  453

4-(1-aminoisoquinolin-5-yl)-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  454

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)pyridin- 4-yl]oxybenzonitrile  455

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(3-oxopiperazin-1- yl)pyridin-4-yl]oxybenzonitrile  456

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-6-(3-oxopiperazin-1- yl)pyridin-4-yl]oxybenzonitrile  457

4-[3-(aminomethyl)-1,2-benzoxazol- 6-yl]-3-(2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  458

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-[2-methoxyethyl(methyl)amino]-6- methylpyridin-4-yl]oxybenzonitrile  459

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-[2-methoxyethyl(methyl)amino]-6- methylpyridin-4-yl]oxybenzonitrile  460

2-amino-3-[1-[4-cyano-2-(5-ethyl-2- methylpyrazol-3-yl)oxyphenyl]indol- 3-yl]propanoic acid  461

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(propan-2- ylamino)pyridin-4-yl]oxybenzonitrile  462

4-[5-(1-aminocyclopropyl)pyrimidin- 2-yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  463

4-[5-(1-aminocyclopropyl)pyrimidin- 2-yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  464

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-6-(4-methyl-3- oxopiperazin-1-yl)pyridin-4- yl]oxybenzonitrile  465

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(4-methyl-3- oxopiperazin-1-yl)pyridin-4- yl]oxybenzonitrile  466

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(6-methylpyridazin-3- yl)pyridin-4-yl]oxybenzonitrile  467

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile  468

4-(5-aminopyrazolo[1,5-a]pyrimidin- 7-yl)-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  469

4-[5-(1-amino-2- hydroxyethyl)pyridin-2-yl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  470

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3R)-3- methylmorpholin-4-yl]pyridin-4- yl]oxybenzonitrile  471

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3S)-3- methylmorpholin-4-yl]pyridin-4- yl]oxybenzonitrile  472

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyridin-2-ylpyrimidin-4- yl)oxybenzonitrile  473

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(oxetan-2- ylmethoxy)pyridin-4- yl]oxybenzonitrile  474

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(5-fluoropyridin-2-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  475

4-(2-amino-[1,2,4]triazolo[1,5- a]pyridin-5-yl)-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  476

4-[5-(2-amino-2- methylpropyl)pyrimidin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  477

4-[5-(2-amino-2- methylpropyl)pyrimidin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  478

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(oxolan-2- ylmethoxy)pyridin-4- yl]oxybenzonitrile  479

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(2-propan-2- yloxyethoxy)pyridin-4- yl]oxybenzonitrile  480

4-[6-(aminomethyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  481

4-[6-(2-aminoethyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  482

4-[4-(2-aminoethyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  483

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(oxolan-2-yl)pyrazol-3- yl]oxybenzonitrile  484

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(oxolan-2-yl)pyrazol-3- yl]oxybenzonitrile  485

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyrazol-3- yl)oxybenzonitrile  486

4-[5-(1-amino-2-oxo-2-piperidin-1- ylethyl)pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  487

4-[5-(1-amino-2-morpholin-4-yl-2- oxoethyl)pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  488

2-amino-2-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-N,N- diethylacetamide  489

2-amino-2-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-N,N- dimethylacetamide  490

2-amino-2-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-N-propan- 2-ylacetamide  491

2-amino-2-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-N- methylacetamide  492

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-(2-methoxyethoxy)-6- methylpyridin-4-yl]oxybenzonitrile  493

4-[5-(aminomethyl)imidazo[1,2- a]pyridin-8-yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  494

4-[5-(aminomethyl)imidazo[1,2- a]pyridin-8-yl]-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile  495

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(oxolan-3-yl)pyrazol-3- yl]oxybenzonitrile  496

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(oxolan-3-yl)pyrazol-3- yl]oxybenzonitrile  497

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[5-methyl-6-[[(3S)-3- methylpiperazin-1- yl]methyl]imidazo[1,2-a]pyridin-8- yl]benzonitrile  498

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-pyrrolidin-1-ylpyridin-4- yl)oxybenzonitrile  499

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(2- methyl-6-pyrrolidin-1-ylpyridin-4- yl)oxybenzonitrile  500

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-piperidin-1-ylpyridin-4- yl)oxybenzonitrile  501

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(2- methyl-6-piperidin-1-ylpyridin-4- yl)oxybenzonitrile  502

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2-(3- fluoroazetidin-1-yl)-6-methylpyridin- 4-yl]oxybenzonitrile  503

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-(3-fluoroazetidin-1-yl)-6- methylpyridin-4-yl]oxybenzonitrile  504

2-amino-2-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]acetamide  505

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- [(2S,6R)-2,6-dimethylmorpholin-4- yl]-6-methylpyridin-4- yl]oxybenzonitrile  506

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- [(2S,6R)-2,6-dimethylmorpholin-4- yl]-6-methylpyridin-4- yl]oxybenzonitrile  507

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-pyrrolidin-1-ylpyrimidin-4- yl)oxybenzonitrile  508

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(2- methyl-6-pyrrolidin-1-ylpyrimidin-4- yl)oxybenzonitrile  509

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-piperidin-1-ylpyrimidin-4- yl)oxybenzonitrile  510

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(2- methyl-6-piperidin-1-ylpyrimidin-4- yl)oxybenzonitrile  511

4-[5-[amino(1H-tetrazol-5- yl)methyl]pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  512

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-pyrimidin-2-ylpyrazol-3- yl)oxybenzonitrile  513

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2-(3- methoxypyridin-2-yl)-6- methylpyridin-4-yl]oxybenzonitrile  514

4-[5-(1-amino-2- hydroxyethyl)pyridin-2-yl]-3-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile  515

4-[3-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  516

2-amino-2-[6-[4-cyano-2-(2-methyl- 5-phenylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]acetamide  517

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  518

4-[4-(2-amino-1-hydroxyethyl)-5- chloropyridin-2-yl]-3-(5-cyclopropyl- 2-methylpyrazol-3-yl)oxybenzonitrile  519

4-[4-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  520

4-[5-(aminomethyl)-1,3-thiazol-2-yl]- 3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  521

4-[5-(aminomethyl)-1,3-thiazol-2-yl]- 3-(2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  522

4-[5-(aminomethyl)imidazo[1,2- a]pyridin-8-yl]-3-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  523

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[6- [(2S,6R)-2,6-dimethylmorpholin-4- yl]-2-methylpyrimidin-4- yl]oxybenzonitrile  524

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[6- [(2S,6R)-2,6-dimethylmorpholin-4- yl]-2-methylpyrimidin-4- yl]oxybenzonitrile  525

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  526

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(2- methyl-6-phenylpyrimidin-4- yl)oxybenzonitrile  527

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyridin- 4-yl]oxybenzonitrile  528

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- methyl-6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]pyridin- 4-yl]oxybenzonitrile  529

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-[(2S)-2-methylmorpholin-4- yl]pyridin-4-yl]oxybenzonitrile  530

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- methyl-6-[(2S)-2-methylmorpholin-4- yl]pyridin-4-yl]oxybenzonitrile  531

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2-(2,2- dimethylmorpholin-4-yl)-6- methylpyridin-4-yl]oxybenzonitrile  532

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- (2,2-dimethylmorpholin-4-yl)-6- methylpyridin-4-yl]oxybenzonitrile  533

4-[3-(1-amino-3-hydroxypropyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  534

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  535

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-morpholin-4-ylpyridazin-3- yl)oxybenzonitrile  536

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-5-(1,3-thiazol-2-yl)pyrazol-3- yl]oxybenzonitrile  537

4-[5-(3-hydroxyazetidin-3-yl)pyridin- 2-yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  538

4-[5-(3-fluoroazetidin-3-yl)pyridin-2- yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  539

4-[5-(3-aminooxan-2-yl)pyridin-2-yl]- 3-(2-methyl-6-morpholin-4-ylpyridin- 4-yl)oxybenzonitrile  540

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-5-pyrimidin-2-ylpyrazol-3- yl)oxybenzonitrile  541

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-piperidin-1-ylpyrazol-3- yl)oxybenzonitrile  542

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-pyrrolidin-1-ylpyrazol-3- yl)oxybenzonitrile  543

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [5-(dimethylamino)-2-methylpyrazol- 3-yl]oxybenzonitrile  544

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-5-pipeddin-1-ylpyrazol-3- yl)oxybenzonitrile  545

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-5-pyrrolidin-1-ylpyrazol-3- yl)oxybenzonitrile  546

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[5- (dimethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  547

N-[5-[2-[5-(2-aminoethyl)pyridin-2- yl]-5-cyanophenoxy]-1- methylpyrazol-3-yl]acetamide  548

N-[5-[2-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-5- cyanophenoxy]-1-methylpyrazol-3- yl]acetamide  549

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-5-(propan-2-ylamino)pyrazol- 3-yl]oxybenzonitrile  550

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-[(3R)-3-methylmorpholin-4- yl]pyridin-4-yl]oxybenzonitrile  551

N-(2-aminoethyl)-2-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridine-4-carboxamide  552

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[4-(piperazine-1- carbonyl)pyridin-2-yl]benzonitrile  553

4-[4-(4-aminopiperidine-1- carbonyl)pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  554

4-[4-[(3R)-3-aminopiperidine-1- carbonyl]pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  555

4-[4-[(3S)-3-aminopiperidine-1- carbonyl]pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  556

4-[4-(2-aminoethoxy)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  557

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (1-methyl-5-morpholin-4-ylpyrazol-3- yl)oxybenzonitrile  558

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-[(2S)-2-methylmorpholin-4- yl]pyrimidin-4-yl]oxybenzonitrile  559

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- methyl-6-[(2S)-2-methylmorpholin-4- yl]pyrimidin-4-yl]oxybenzonitrile  560

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[6-(2,2- dimethylmorpholin-4-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  561

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[6- (2,2-dimethylmorpholin-4-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  562

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-(2-methyl- 6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  563

4-[5-(azetidin-3-yloxy)pyrimidin-2- yl]-3-(2-methyl-6-morpholin-4 ylpyridin-4-yl)oxybenzonitrile  564

4-[5-(azetidin-3-yloxy)pyridin-2-yl]- 3-(2-methyl-6-morpholin-4-ylpyridin- 4-yl)oxybenzonitrile  565

4-[5-[(3S)-3-amino-2-oxopyrrolidin- 1-yl]pyridin-2-yl]-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile  566

4-[1-(2-aminoethyl)-2-oxopyridin-4- yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  567

4-[2-(2-aminoethoxy)pyridin-4-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  568

4-[5-(4-amino-2-oxopyrrolidin-1- yl)pyridin-2-yl]-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile  569

4-[5-[(3R)-3-amino-2-oxopyrrolidin- 1-yl]pyridin-2-yl]-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile  570

4-[3-(2-aminoethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  571

4-[3-(azetidin-3-yl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  572

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyridin-2-ylpyridin-4- yl)oxybenzonitrile  573

4-[1-(2-aminoethyl)-2-oxopyridin-3- yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  574

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- methyl-5-(1,3-thiazol-2-yl)pyrazol-3- yl]oxybenzonitrile  575

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(propan-2- ylamino)pyrazol-3-yl]oxybenzonitrile  576

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(5- amino-2-methylpyrazol-3- yl)oxybenzonitrile  577

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-amino-2-methylpyrazol-3- yl)oxybenzonitrile  578

4-[4-(3-aminopropyl)phenyl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  579

4-[4-(3-aminopropyl)phenyl]-3-(2- methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  580

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(oxan-4-yl)pyridin-4- yl]oxybenzonitrile  581

2-amino-3-[8-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]-[1,2,4]triazolo[4,3- a]pyridin-3-yl]propanoic acid  582

4-[5-(aminomethyl)-1,3,4-thiadiazol- 2-yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  583

4-[5-(aminomethyl)-1,3,4-thiadiazol- 2-yl]-3-(2-methyl-5-phenylpyrazol-3- yl)oxybenzonitrile  584

4-[5-(aminomethyl)-1,3-oxazol-2-yl]- 3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  585

4-[4-(3-aminopropoxy)pyridin-2-yl]- 3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  586

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[4-(3- hydroxypropylamino)pyridin-2- yl]benzonitrile  587

4-[4-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  588

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-5-(1,3-oxazol-2-yl)pyrazol-3- yl]oxybenzonitrile  589

4-[5-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  590

4-[5-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  591

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(oxetan-3-yloxy)pyridin-4- yl]oxybenzonitrile  592

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1,3-thiazol-2-yl)pyrazol- 3-yl]oxybenzonitrile  593

4-[5-(aminomethyl)-1,3,4-thiazol-2- yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  594

4-(3-amino-1,2-benzoxazol-7-yl)-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  595

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(1,3-thiazol-2-yl)pyridin- 4-yl]oxybenzonitrile  596

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(1,3-oxazol-2-yl)pyridin- 4-yl]oxybenzonitrile  597

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyrazin-2-ylpyridin-4- yl)oxybenzonitrile  598

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(1,3-thiazol-2- yl)pyrimidin-4-yl]oxybenzonitrile  599

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyridin-2-ylpyrimidin-4- yl)oxybenzonitrile  600

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- methyl-6-(4-methyl-1,3-thiazol-2- yl)pyridin-4-yl]oxybenzonitrile  601

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[2- methyl-6-(5-methyl-1,3-thiazol-2- yl)pyridin-4-yl]oxybenzonitrile  602

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(5-methyl-1,3-thiazol-2- yl)pyrimidm-4-yl]oxybenzonitrile  603

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(1,3-thiazol-2-yl)pyrimidin- 4-yl]oxybenzonitrile  604

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-pyridin-2-ylpyrimidin-4- yl)oxybenzonitrile  605

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(5-methyl-1,3-thiazol-2- yl)pyridin-4-yl]oxybenzonitrile  606

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(5-methyl-1,3-thiazol-2- yl)pyrimidin-4-yl]oxybenzonitrile  607

4-[2-(aminomethyl)-1,3-thiazol-5-yl]- 3-(2-methyl-6-morpholin-4-ylpyridin- 4-yl)oxybenzonitrile  608

4-[2-(aminomethyl)-1,3-thiazol-5-yl]- 3-(2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  609

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  610

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  611

(2S)-2-amino-3-[6-[4-cyano-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]propanoic acid  612

(2S)-2-amino-3-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]propanoic acid  613

4-[5-[3-(aminomethyl)oxetan-3- yl]pyridin-2-yl]-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile  614

(2R)-2-amino-3-[6-[4-cyano-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]propanoic acid  615

(2R)-2-amino-3-[6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]propanoic acid  616

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-(2-methyl- 6-pyrrolidin-1-ylpyrimidin-4- yl)oxybenzonitrile  617

4-[3-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  618

3-(aminomethyl)-6-[4-cyano-2-(5- cyclopropyl-2-methylpyrazol-3- yl)oxyphenyl]pyridine-2-carboxylic acid  619

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)oxybenzonitrile  620

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)oxybenzonitrile  621

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-piperidin-1-ylpyrazol-3- yl)oxybenzonitrile  622

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-pyrrolidin-1-ylpyrazol-3- yl)oxybenzonitrile  623

4-[5-(aminomethyl)pyridin-2-yl]-3- [5-(dimethylamino)-2-methylpyrazol- 3-yl]oxybenzonitrile  624

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-piperidin-1-ylpyrazol-3- yl)oxybenzonitrile  625

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrrolidin-1-ylpyrazol-3- yl)oxybenzonitrile  626

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(dimethylamino)-2-methylpyrazol- 3-yl]oxybenzonitrile  627

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-piperidin-1-ylpyrazol-3- yl)oxybenzonitrile  628

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrrolidin-1-ylpyrazol-3- yl)oxybenzonitrile  629

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-(dimethylamino)-2-methylpyrazol- 3-yl]oxybenzonitrile  630

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(propan-2- ylamino)pyrimidin-4 yl]oxybenzonitrile  631

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(ethylamino)-2-methylpyrimidin-4- yl]oxybenzonitrile  632

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(propylamino)pyrimidin- 4-yl]oxybenzonitrile  633

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(cyclopropylamino)-2- methylpyrimidin-4-yl]oxybenzonitrile  634

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2- methylpropylamino)pyrimidin-4- yl]oxybenzonitrile  635

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(oxan-4 ylamino)pyrimidin-4- yl]oxybenzonitrile  636

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(oxan-4- ylmethylamino)pyrimidin-4- yl]oxybenzonitrile  637

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(tert-butylamino)-2- methylpyrimidin-4-yl]oxybenzonitrile  638

4-[4-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  639

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2-methoxyethylamino)-2- methylpyrimidin-4-yl]oxybenzonitrile  640

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2,2,2- trifluoroethylamino)pyrimidin-4- yl]oxybenzonitrile  641

4-[5-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  642

4-[4-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  643

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-(ethylamino)-6-methylpyridin-4- yl]oxybenzonitrile  644

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(propan-2- ylamino)pyridin-4-yl]oxybenzonitrile  645

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-(cyclopropylamino)-6- methylpyridin-4-yl]oxybenzonitrile  646

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-(cyclopropylamino)-6- methylpyridin-4-yl]oxybenzonitrile  647

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-methyl-6-(oxan-4-ylamino)pyridin- 4-yl]oxybenzonitrile  648

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(oxan-4-ylamino)pyridin- 4-yl]oxybenzonitrile  649

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(3-fluoropyridin-2-yl)-2- methylpyrazol-3-yl]oxybenzonitrile  650

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(6-methylpyridin-2- yl)pyrazol-3-yl]oxybenzonitrile  651

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(5-fluoropyridin-2-yl)-2- methylpyrazol-3-yl]oxybenzonitrile  652

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(4-methylpyridin-2- yl)pyrazol-3-yl]oxybenzonitrile  653

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(3,3-difluoroazetidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  654

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-6-(4- methylsulfonylpiperazin-1- yl)pyrimidin-4-yl]oxybenzonitrile  655

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(diethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  656

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-(diethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  657

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyrimidin- 4-yl)oxybenzonitrile  658

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyrimidin- 4-yl)oxybenzonitrile  659

4-[5-(aminomethyl)pyridin-2-yl]-3- [6-(dimethylamino)-2- methylpyrimidin-4-yl]oxybenzonitrile  660

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(dimethylamino)-2- methylpyrimidin-4-yl]oxybenzonitrile  661

4-[5-[(tert- butylamino)methyl]pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  662

4-[5- [(cyclopropylamino)methyl]pyrimidin- 2-yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile  663

3-(2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxy-4-[5-[(propan-2- ylamino)methyl]pyrimidin-2- yl]benzonitrile  664

4-[5-[(tert- butylamino)methyl]pyrimidin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  665

4-[5-[[(3-methyloxetan-3- yl)amino]methyl]pyrimidin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  666

4-[5-[(1- adamantylamino)methyl]pyrimidin-2- yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile  667

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-[6-(4- fluoropiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  668

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(4-fluoropiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  669

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(4-fluoropiperidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  670

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-[6-(7- azabicyclo[2.2.1]heptan-7-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  671

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(7-azabicyclo[2.2.1]heptan-7-yl)- 2-methylpyrimidin-4- yl]oxybenzonitrile  672

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(7-azabicyclo[2.2.1]heptan-7-yl)- 2-methylpyrimidin-4- yl]oxybenzonitrile  673

(2S)-1-[6-[2-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-5- cyanophenoxy]-2-methylpyrimidin-4- yl]pyrrolidine-2-carbonitrile  674

(2S)-1-[6-[2-[5-(2- aminoethyl)pyrimidin-2-yl]-5- cyanophenoxy]-2-methylpyrimidin-4- yl]pyrrolidine-2-carbonitrile  675

(2S)-1-[6-[2-[5- (aminomethyl)pyrimidin-2-yl]-5- cyanophenoxy]-2-methylpyrimidin-4- yl]pyrrolidine-2-carbonitrile  676

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-methyl-1,2-oxazol-3- yl)oxy]benzonitrile  677

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-methyl-1,2-oxazol-3- yl)oxy]benzonitrile  678

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-5,6-dihydro-4H- cyclopenta[c]pyrazol-3- yl)oxy]benzonitrile  679

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-6,7-dihydro-4H- pyrano[4,3-c]pyrazol-3- yl)oxy]benzonitrile  680

4-[4-(aminomethyl)pyrimidin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  681

4-[4-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  682

4-[4-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  683

4-[4-(2-aminoethyl)pyridin-2-yl]-3- [(2-methyl-5,6-dihydro-4H- cyclopenta[c]pyrazol-3- yl)oxy]benzonitrile  684

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-4,5.6,7-tetrahydroindazol- 3-yl)oxy]benzonitrile  685

4-[4-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-4,5,6,7-tetrahydroindazol- 3-yl)oxy]benzonitrile  686

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyrimidin-2-ylpyridin-4- yl)oxybenzonitrile  687

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(1-methylimidazol-2- yl)pyridin-4-yl]oxybenzonitrile  688

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-(2- methyl-6-pyridin-2-ylpyridin-4- yl)oxybenzonitrile  689

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(1,3-thiazol-2-yl)pyridin-4- yl]oxybenzonitrile  690

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(1,3-oxazol-2-yl)pyridin-4- yl]oxybenzonitrile  691

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-pyridin-2-ylpyridin-4- yl)oxybenzonitrile  692

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-pyrimidin-2-ylpyridin-4- yl)oxybenzonitrile  693

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-(2- methyl-6-pyrazin-2-ylpyridin-4- yl)oxybenzonitrile  694

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[2- methyl-6-(4-methyl-1,3-thiazol-2- yl)pyridin-4-yl]oxybenzonitrile  695

4-[5-(aminomethyl)pyridin-2-yl]-3- (6-cyclopropylpyridazin-4- yl)oxybenzonitrile  696

4-[5-(aminomethyl)pyridin-2-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)oxybenzonitrile  697

4-[5-(aminomethyl)pyridin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)oxybenzonitrile  698

4-[5-(aminomethyl)pyridin-2-yl]-3- [6-(dimethylamino)pyridazin-4- yl]oxybenzonitrile  699

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-pyridin-2-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  700

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-bromo-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  701

4-[5-(1-aminoethypyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  702

4-[5-(1-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  703

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-pyridin-2-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  704

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-piperidin-1-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  705

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-phenyl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  706

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-phenyl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  707

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-piperidin-1-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  708

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(2S)-2- methylmorpholin-4-yl]pyrimidin-4- yl]oxybenzonitrile  709

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-[(2R,6S)-2,6-dimethylmorpholin- 4-yl]-2-methylpyrimidin-4- yl]oxybenzonitrile  710

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2,2-dimethylmorpholin-4-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  711

4-[5-(aminomethyl)imidazo[1,2- a]pyridin-8-yl]-3-(2-methyl-5-propan- 2-ylpyrazol-3-yl)oxybenzonitrile  712

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[5-(trifluoromethyl)-1,3,4-thiadiazol- 2-yl]oxy]benzonitrile  713

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-cyclopropylpyridazin-4- yl)oxybenzonitrile  714

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)oxybenzonitrile  715

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)oxybenzonitrile  716

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(dimethylamino)pyridazin-4- yl]oxybenzonitrile  717

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(5-morpholin-4-yl-1,3,4-thiadiazol- 2-yl)oxy]benzonitrile  718

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(5-cyclopropyl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  719

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(5-pyrrolidin-1-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  720

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[5-(azetidin-1-yl)-1,3,4-thiadiazol-2- yl]oxy]benzonitrile  721

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[5-(3-fluoroazetidin-1-yl)-1,3,4- thiadiazol-2-yl]oxy]benzonitrile  722

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[5-(3-fluoroazetidin-1-yl)-1,3,4- thiadiazol-2-yl]oxy]benzonitrile  723

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-morpholin-4-yl-1,3,4-thiadiazol- 2-yl)oxy]benzonitrile  724

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[5-(diethylamino)-1,3,4-thiadiazol-2- yl]oxy]benzonitrile  725

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-pyrrolidin-1-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  726

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-pyrrolidin-1-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  727

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[5-(dimethylamino)-1,3,4-thiadiazol- 2-yl]oxy]benzonitrile  728

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-cyclopropyl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  729

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-pyridin-3-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  730

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-pyridin-4-yl-1,3,4-thiadiazol-2- yl)oxy]benzonitrile  731

4-[6-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  732

4-[6-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  733

4-[6-(aminomethyl)- [1,2,4]triazolo[4,3-a]pyridin-8-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  734

4-[5-(1-aminopropyl)pyrimidin-2-yl]- 3-(2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  735

4-[5-(1-aminopropyl)pyrimidin-2-yl]- 3-(2-methyl-6-morpholin-4-ylpyridin- 4-yl)oxybenzonitrile  736

4-[6-(aminomethyl)imidazo[1,2- a]pyridin-8-yl]-3-(5-cyclopropyl-2- methylpyrazol-3-yl)oxybenzonitrile  737

4-[6-(aminomethyl)imidazo[1,2- a]pyridin-8-yl]-3-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  738

4-[2-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-5- cyanophenoxy]-6-pyrrolidin-1- ylpyridine-3-carbonitrile  739

4-[2-[5-(2-aminoethyl)pyrimidin-2- yl]-5-cyanophenoxy]-6-pyrrolidin-1- ylpyridine-3-carbonitrile  740

4-[2-[5-(aminomethyl)pyrimidin-2- yl]-5-cyanophenoxy]-6-pyrrolidin-1- ylpyridine-3-carbonitrile  741

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-(2-methyl- 5-pyrrolidin-1-ylpyrazol-3- yl)oxybenzonitrile  742

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-(2-methyl- 5-piperidin-1-ylpyrazol-3- yl)oxybenzonitrile  743

4-[5-[(3-aminooxetan-3- yl)methyl]pyridin-2-yl]-3-[5- (dimethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  744

3-(2-methyl-6-piperidin-1- ylpyrimidin-4-yl)oxy-4-(4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-2- yl)benzonitrile  745

3-(2-methyl-6-piperidin-1- ylpyrimidin-4-yl)oxy-4-(4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-1- yl)benzonitrile  746

3-(2-methyl-6-piperidin-1- ylpyrimidin-4-yl)oxy-4-(4,5,6,7- tetrahydropyrazolo[3,4-c]pyridin-2- yl)benzonitrile  747

3-(2-methyl-6-piperidin-1- ylpyrimidin-4-yl)oxy-4-(4,5,6,7- tetrahydropyrazolo[3,4-c]pyridin-1- yl)benzonitrile  748

4-[2-[5-(2-aminoethyl)pyrimidin-2- yl]-5-cyanophenoxy]-6-(7- azabicyclo[2.2.1]heptan-7- yl)pyridine-3-carbomtrile  749

4-[2-[5-(aminomethyl)pyrimidin-2- yl]-5-cyanophenoxy]-6-(7- azabicyclo[2.2.1]heptan-7- yl)pyridine-3-carbonitrile  750

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-pyrrolidin-1-ylpyridin-3- yl)oxybenzonitrile  751

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-pyrrolidin-1-ylpyridin-3- yl)oxybenzonitrile  752

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(7-azabicyclo[2.2.1]heptan-7- yl)pyridin-3-yl]oxybenzonitrile  753

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(7-azabicyclo[2.2.1]heptan-7- yl)pyridin-3-yl]oxybenzonitrile  754

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [5-(diethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  755

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(2-oxopyrrolidin-1- yl)pyrazol-3-yl]oxybenzonitrile  756

4-[6-[(3S)-3-aminopiperidine-1- carbonyl]imidazo[1,2-a]pyridin-8-yl]- 3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  757

4-[6-[(3R)-3-aminopiperidine-1- carbonyl]imidazo[1,2-a]pyridin-8-yl]- 3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  758

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-[methyl(2- methylpropyl)amino]pyrazol-3- yl]oxybenzonitrile  759

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-(dipropylamino)-2-methylpyrazol- 3-yl]oxybenzonitrile  760

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[2-methoxyethyl(methyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  761

4-(4-chloro-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2- yl)-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl))oxybenzonitrile  762

4-[4-(dimethylamino)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-2- yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile  763

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazin-3- yl)benzonitrile  764

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(propan-2-ylamino)pyridazin-4- yl]oxybenzonitrile  765

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2-methylpropylamino)pyridazin- 4-yl]oxybenzonitrile  766

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(oxetan-3-ylamino)pyridazin-4- yl]oxybenzonitrile  767

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[5-(7-azabicyclo[2.2.1]heptan-7-yl)- 1,3,4-thiadiazol-2-yl]oxy]benzonitrile  768

4-[5-(1-amino-2- methylpropyl)pyrimidin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile  769

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5- [cyclopropylmethyl(methyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  770

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5- [methyl(propyl)amino]pyrazol-3- yl]oxybenzonitrile  771

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyrazol-3- yl)oxybenzonitrile  772

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyrazol-3- yl)oxybenzonitrile  773

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyrazol-3- yl)oxybenzonitrile  774

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[ethyl(methyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  775

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-[methyl(propan-2- yl)amino]pyrazol-3- yl]oxybenzonitrile  776

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-(4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-2- yl)benzonitrile  777

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-(4,5,6,7- tetrahydropyrazolo[4,3-c]pyridin-1- yl)benzonitrile  778

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[5-[(2-oxopiperazin-1- yl)methyl]pyridin-2-yl]benzonitrile  779

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[5-(piperazin-1- ylmethyl)pyridin-2-yl]benzonitrile  780

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[5-(piperazine-1- carbonyl)pyridin-2-yl]benzonitrile  781

N-[6-[4-cyano-2-(5-cyclopropyl-2- methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]piperidine- 4-carboxamide  782

N-[6-[4-cyano-2-(5-cyclopropyl-2- methylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-N- methylpiperidine-4-carboxamide  783

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[5-(2-oxo-2-piperazin-1- ylethyl)pyridin-2-yl]benzonitrile  784

3-(5-cyclopropyl-2-methylpyrazol-3- yl)oxy-4-[6-[2- (dimethylamino)ethoxy]pyridazin-3- yl]benzonitrile  785

4-[4-(2-aminoethyl)phenyl]-3-[[2- piperidin-1-yl-4(trifluoromethyl)- 1,3-thiazol-5-yl]oxy]benzonitrile  786

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[2,2-difluoroethyl(methyl)amino]- 2-methylpyrazol-3-yl]oxybenzonitrile  787

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-[methyl(2,2,2- trifluoroethyl)amino]pyrazol-3- yl]oxybenzonitrile  788

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-cyclobutyloxy-2-methylpyrimidin- 4-yl)oxybenzonitrile  789

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(azetidin-1-yl)-2-methylpyrimidin- 4-yl]oxybenzonitrile  790

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-[ethyl(methyl)amino]-2- methylpyrimidin-4-yl]oxybenzonitrile  791

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(diethylamino)-2-methylpyrimidin- 4-yl]oxybenzonitrile  792

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[methyl(propan-2- yl)amino]pyrimidin-4- yl]oxybenzonitrile  793

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(3-fluoroazetidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  794

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(2R)-2- methylpyrrolidin-1-yl]pyrimidin-4- yl]oxybenzonitrile  795

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(2S)-2- methylpyrrolidin-1-yl]pyrimidin-4- yl]oxybenzonitrile  796

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6- [cyclopropylmethyl(methyl)amino]-2- methylpyrimidin-4-yl]oxybenzonitrile  797

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-[2-methoxyethyl(methyl)amino]-2- methylpyrimidin-4-yl]oxybenzonitrile  798

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-[2-methoxyethyl(methyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  799

4-[5-(aminomethyl)pyridin-2-yl]-3- [5-[2-methoxyethyl(methyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  800

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[3-methoxypropyl(methyl)amino]- 2-methylpyrazol-3-yl]oxybenzonitrile  801

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [3-methyl-1-(2-methylpropyl)pyrazol- 4-yl]oxybenzonitrile  802

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [3-methyl-1-(2-methylpropyl)pyrazol- 4-yl]oxybenzonitrile  803

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (3-methyl-1-propan-2-ylpyrazol-4- yl)oxybenzonitrile  804

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-methyl-1-(2-methylpropyl)pyrazol- 4-yl]oxybenzonitrile  805

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-methyl-1-(2-methylpropyl)pyrazol- 4-yl]oxybenzonitrile  806

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-methyl-1-propan-2-ylpyrazol-4- yl)oxybenzonitrile  807

5-[2-[4-(2-aminoethyl)phenyl]-5- cyanophenoxy]-2-phenyl-1,3- thiazole-4-carbonitrile  808

4-[5-[(1R)-1-aminoethyl]pyrimidin-2- yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile  809

4-[5-[(1S)-1-aminoethyl]pyrimidin-2- yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile  810

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-methyl-5-(trifluoromethyl)pyrazol- 3-yl]oxybenzonitrile  811

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(trifluoromethyl)pyrazol- 3-yl]oxybenzonitrile  812

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(tritluoromethyl)pyrazol- 3-yl]oxybenzonitrile  813

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-methyl-5-propan-2-yl-1,2,4- triazol-3-yl)oxy]benzonitrile  814

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-5-propan-2-yl-1,2,4- triazol-3-yl)oxy]benzonitrile  815

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (3-chloro-6-piperidin-1-ylpyridazin- 4-yl)oxybenzonitrile  816

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-chloro-3-piperidin-1-ylpyridazin- 4-yl)oxybenzonitrile  817

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-pyridin-2-ylpyridazin-4 yl)oxybenzonitrile  818

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-cyclopentyloxypyridazin-4- yl)oxybenzonitrile  819

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2-methylpropoxy)pyridazin-4- yl]oxybenzonitrile  820

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2-oxopyridin-1-yl)pyridazin-4- yl]oxybenzonitrile  821

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (3-methyl-6-piperidin-1-ylpyridazin- 4-yl)oxybenzonitrile  822

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[2-fluoroethyl(methyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  823

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[bis(2-fluoroethyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  824

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (3-methyl-6-pyrrolidin-1-ylpyridazin- 4-yl)oxybenzonitrile  825

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (3-methyl-6-morpholin-4-ylpyridazin- 4-yl)oxybenzonitrile  826

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-(7-azabicyclo[2.2.1]heptan-7-yl)- 6-methylpyridin-4-yl]oxybenzonitrile  827

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-(7-azabicyclo[2.2.1]heptan-7-yl)- 6-methylpyridin-4-yl]oxybenzonitrile  828

4-[5-(aminomethyl)pyridin-2-yl]-3- [5-(difluoromethyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  829

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(difluoromethyl)-2-methylpyrazol- 3-yl]oxybenzonitrile  830

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-methyl-1-pyridin-2-ylpyrazol-4- yl)oxybenzonitrile  831

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-methyl-1-pyridin-2-ylpyrazol-4- yl)oxybenzonitrile  832

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (3-methyl-1-pyridin-2-ylpyrazol-4- yl)oxybenzonitrile  833

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (3-methyl-1-pyridin-2-ylpyrazol-4 yl)oxybenzonitrile  834

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [3-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxybenzonitrile  835

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [3-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxybenzonitrile  836

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxybenzonitrile  837

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxybenzonitrile  838

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[4-methoxybutyl(methyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  839

2-[[1-[6-[4-cyano-2-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-2- methylpropan-2-yl]amino]-N,N- dimethylacetamide  840

2-[[1-[6-[4-cyano-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]-2- methylpropan-2-yl]amino]-N,N- dimethylacetamide  841

2-[[2-[4-cyano-2-(2-methyl-6-pyridin- 2-ylpyridin-4- yl)oxyphenyl]pyrimidin-5- yl]methylamino]acetamide  842

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[ethyl(propan-2-yl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  843

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2-methoxyethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  844

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3R)-oxolan-3- yl]oxypyrimidin-4-yl]oxybenzonitrile  845

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3S)-oxolan-3- yl]oxypyrimidin-4-yl]oxybenzonitrile  846

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2- methylpropoxy)pyrimidin-4- yl]oxybenzonitrile  847

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-[(2,2- difluorocyclopropyl)methoxy]-2- methylpyrimidin-4-yl]oxybenzonitrile  848

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-propan-2- yloxypyrimidin-4-yl)oxybenzonitrile  849

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2- methylpropoxy)pyrimidin-4- yl]oxybenzonitrile  850

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(5,6-dihydro-4H-pyrimidin-1-yl)- 2-methylpyrimidin-4- yl]oxybenzonitrile  851

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2-oxopyrrolidin-1- yl)pyrimidin-4-yl]oxybenzonitrile  852

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[methyl(oxetan-3- yl)amino]pyrimidin-4- yl]oxybenzonitrile  853

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(azetidin-1-yl)-2-methylpyrimidin- 4-yl]oxybenzonitrile  854

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-[ethyl(methyl)amino]-2- methylpyrimidin-4-yl]oxybenzonitrile  855

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2-oxoazetidin-1- yl)pyrimidin-4-yl]oxybenzonitrile  856

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(diethylamino)-2-methylpyrimidin- 4-yl]oxybenzonitrile  857

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[methyl(propan-2- yl)amino]pyrimidin-4- yl]oxybenzonitrile  858

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(3-fluoroazetidin-1-yl)-2- methylpyrimidin-4-yl]oxybenzonitrile  859

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(2R)-2- methylpyrrolidin-1-yl]pyrimidin-4- yl]oxybenzonitrile  860

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(2S)-2- methylpyrrolidin-1-yl]pyrimidin-4- yl]oxybenzonitrile  861

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6- [cyclopropylmethyl(methyl)amino]-2- methylpyrimidin-4-yl]oxybenzonitrile  862

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-[2-methoxyethyl(methyl)amino]-2- methylpyrimidin-4-yl]oxybenzonitrile  863

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-[methyl(2-propan-2- yloxyethyl)amino]pyrazol-3- yl]oxybenzonitrile  864

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (1-cyclohexyl-3-methylpyrazol-4- yl)oxybenzonitrile  865

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (1-cyclohexyl-3-methylpyrazol-4- yl)oxybenzonitrile  866

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(3,3,4,4- tetrafluoropyrrolidin-1-yl)pyrazol-3- yl]oxybenzonitrile  867

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-[(2-methoxy-2-methylpropyl)- methylamino]-2-methylpyrazol-3- yl]oxybenzonitrile  868

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[(2-methoxy-2-methylpropyl)- methylamino]-2-methylpyrazol-3- yl]oxybenzonitrile  869

4-[5-[(4R)-3-amino-4-fluoropiperidin- 1-yl]pyridin-2-yl]-3-(5-cyclopropyl- 2-methylpyrazol-3-yl)oxybenzonitrile  870

4-[6-(aminomethyl)pyridazin-3-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  871

4-[6-(aminomethyl)pyridazin-3-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  872

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  873

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-[2,2-difluoroethyl(methyl)amino]- 2-methylpyrazol-3-yl]oxybenzonitrile  874

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-[2,2-difluoroethyl(ethyl)amino]-2- methylpyrazol-3-yl]oxybenzonitrile  875

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[2,2-difluoroethyl(ethyl)amino]-2 methylpyrazol-3-yl]oxybenzonitrile  876

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  877

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(3,3,4,4- tetrafluoropyrrolidin-1-yl)pyrazol-3- yl]oxybenzonitrile  878

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile  879

4-[5-(2-aminoethyl)pyrimidm-2-yl]-3- [2-methyl-6-[methyl(oxetan-3- yl)amino]pyrimidin-4- yl]oxybenzonitrile  880

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2-oxopyrrolidin-1- yl)pyrimidin-4-yl]oxybenzonitrile  881

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(5,6-dihydro-4H-pyrimidin-1-yl)- 2-methylpyrimidin-4- yl]oxybenzonitrile  882

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2-oxoazetidin-1- yl)pyrimidin-4-yl]oxybenzonitrile  883

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-[(2,2- difluorocyclopropyl)methoxy]-2- methylpyrimidin-4-yl]oxybenzonitrile  884

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2,2,2- trifluoroethoxy)pyrimidin-4- yl]oxybenzonitrile  885

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3-methyloxetan-3- yl)methoxy]pyrimidin-4- yl]oxybenzonitrile  886

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-(oxetan-3- yloxy)pyrimidin-4-yl]oxybenzonitrile  887

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-cyclobutyloxy-2-methylpyrimidin- 4-yl)oxybenzonitrile  888

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3S)-oxolan-3- yl]oxypyrimidin-4-yl]oxybenzonitrile  889

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3R)-oxolan-3- yl]oxypyrimidin-4-yl]oxybenzonitrile  890

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(2-methoxyethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  891

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [6-(2,2-difluoroethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  892

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-cyclopropyloxy-2- methylpyrimidin-4-yl)oxybenzonitrile  893

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(2,2,2- trifluoroethoxy)pyrimidin-4- yl]oxybenzonitrile  894

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-[(3-methyloxetan-3- yl)methoxy]pyrimidin-4- yl]oxybenzonitrile  895

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-6-(oxetan-3- yloxy)pyrimidin-4-yl]oxybenzonitrile  896

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-propan-2- yloxypyrimidin-4-yl)oxybenzonitrile  897

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2,2-difluoroethoxy)-2- methylpyrimidin-4-yl]oxybenzonitrile  898

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-cyclopropyloxy-2- methylpyrimidin-4-yl)oxybenzonitrile  899

4-[5-(aminomethyl)pyrimidin-2-yl]-2- methyl-5-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  900

4-[5-(2-aminoethyl)pyrimidin-2-yl]-2- methyl-5-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile  901

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-methyl-2-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  902

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-methyl-2-morpholin-4-ylpyridin-4- yl)oxybenzonitrile  903

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[2- methyl-5-(trifluoromethyl)pyrazol-3- yl]oxybenzonitrile  904

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[2- methyl-5-(trifluoromethyl)pyrazol-3- yl]oxybenzonitrile  905

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[5- (dimethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  906

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[5- (dimethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  907

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2-methylpropyl)pyrazol-4- yl]oxybenzonitrile  908

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [1-(2-methylpropyl)pyrazol-4- yl]oxybenzonitrile  909

4-[5-[(1S)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-[5- (dimethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  910

4-[5-[(1R)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-[5- (dimethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  911

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2,2,2-trifluoroethyl)pyrazol-4- yl]oxybenzonitrile  912

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (1-pyridin-2-ylpyrazol-4- yl)oxybenzonitrile  913

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[5- (diethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  914

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[5- (diethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  915

4-[5-[(1S)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-[5- (diethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  916

4-[5-[(1R)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-[5- (diethylamino)-2-methylpyrazol-3- yl]oxybenzonitrile  917

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-morpholin-4-ylpyridin-3- yl)oxybenzonitrile  918

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-morpholin-4-ylpyridin-3- yl)oxybenzonitrile  919

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyridin-3- yl)oxybenzonitrile  920

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyridin-3- yl)oxybenzonitrile  921

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-3- yl)oxybenzonitrile  922

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-3- yl)oxybenzonitrile  923

4-[5-(2-aminoacetyl)pyridin-2-yl]-3- (5-cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile  924

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2,2-difluoroethyl)-3- methylpyrazol-4-yl]oxybenzonitrile  925

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2,2-difluoroethyl)-5- methylpyrazol-4-yl]oxybenzonitrile  926

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-prop-2-ynoxypyrimidin- 4-yl)oxybenzonitrile  927

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2,2-difluoroethyl)pyrazol-4- yl]oxybenzonitrile  928

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(5-fluoropyridin-3-yl)-2- methylpyrazol-3-yl]oxybenzonitrile  929

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-bromo-2-methylpyrazol-3- yl)oxybenzonitrile  930

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrimidin-5-ylpyrazol-3- yl)oxybenzonitrile  931

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrazin-2-ylpyrazol-3- yl)oxybenzonitrile  932

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrimidin-4-ylpyrazol-3- yl)oxybenzonitrile  933

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(1,2-dimethylimidazol-4-yl)-2- methylpyrazol-3-yl]oxybenzonitrile  934

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyridazin-3-ylpyrazol-3- yl)oxybenzonitrile  935

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1,3-thiazol-5-yl)pyrazol- 3-yl]oxybenzonitrile  936

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1-methylimidazol-2- yl)pyrazol-3-yl]oxybenzonitrile  937

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2,2-dimethylpropyl)-3- methylpyrazol-4-yl]oxybenzonitrile  938

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2,2-dimethylpropyl)-5- methylpyrazol-4-yl]oxybenzonitrile  939

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [3,5-dimethyl-1-(2- methylpropyl)pyrazol-4- yl]oxybenzonitrile  940

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2,2-difluoroethyl)-3,5- dimethylpyrazol-4-yl]oxybenzonitrile  941

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (3,5-dimethyl-1-pyridin-2-ylpyrazol- 4-yl)oxybenzonitrile  942

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (3,5-dimethyl-1-propan-2-ylpyrazol- 4-yl)oxybenzonitrile  943

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [3,5-dimethyl-1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxybenzonitrile  944

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)pyrazol- 3-yl]oxybenzonitrile  945

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(2-methylpyrazol-3- yl)pyrazol-3-yl]oxybenzonitrile  946

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1-methylpyrazol-3- yl)pyrazol-3-yl]oxybenzonitrile  947

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1-methylpyrazol-4- yl)pyrazol-3-yl]oxybenzonitrile  948

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1,3-thiazol-4-yl)pyrazol- 3-yl]oxybenzonitrile  949

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrimidin-4-ylpyrazol-3- yl)oxybenzonitrile  950

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrazin-2-ylpyrazol-3- yl)oxybenzonitrile  951

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1,3-thiazol-5-yl)pyrazol- 3-yl]oxybenzonitrile  952

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-methyl-5-(1,3-thiazol-4-yl)pyrazol- 3-yl]oxybenzonitrile  953

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [3-ethyl-1-(2-methylpropyl)pyrazol-4- yl]oxybenzonitrile  954

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-ethyl-1-(2-methylpropyl)pyrazol-4- yl]oxybenzonitrile  955

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2-methylpropyl)-3- (trifluoromethyl)pyrazol-4- yl]oxybenzonitrile  956

5-[2-[5-(aminomethyl)pyrimidin-2- yl]-5-cyanophenoxy]-N,N,1- trimethylpyrazole-3-carboxamide  957

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(2-methyl-1,3-thiazol-4- yl)pyrazol-3-yl]oxybenzonitrile  958

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(4-methyl-1,3-thiazol-5- y)pyrazol-3-yl]oxybenzonitrile  959

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(4-methyl-1,3-thiazol-2- yl)pyrazol-3-yl]oxybenzonitrile  960

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(5-methyl-1,3-thiazol-2- yl)pyrazol-3-yl]oxybenzonitrile  961

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(5-methyl-1,3,4- thiadiazol-2-yl)pyrazol-3- yl]oxybenzonitrile  962

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(2-methyl-1,3-thiazol-5- yl)pyrazol-3-yl]oxybenzonitrile  963

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-(5-methyl-1,3-thiazol-4- yl)pyrazol-3-yl]oxybenzonitrile  964

5-[2-[5-(2-aminoethyl)pyridin-2-yl]- 5-cyanophenoxy]-1-methylpyrazole- 3-carbonitrile  965

2-[2-[4-fluoro-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  966

2-[2-[4-fluoro-2-[3-methyl-1-(2- methylpropyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine  967

2-[2-[4-fluoro-2-[5-methyl-1-(2- methylpropyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine  968

2-[2-[4-fluoro-2-[3-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine  969

2-[2-[4-fluoro-2-(3-methyl-1-pyridin- 2-ylpyrazol-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  970

2-[2-[4-fluoro-2-[5-methyl-1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine  971

2-[2-[4-fluoro-2-(5-methyl-1-pyridin- 2-ylpyrazol-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  972

5-[2-[5-(2-aminoethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N,N-diethyl-1- methylpyrazole-3-amine  973

2-[2-[4-fluoro-2-(2-methyl-5- morpholin-4-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  974

[2-[4-fluoro-2-(2-methyl-5- morpholin-4-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]methanamine  975

2-[6-[4-fluoro-2-(2-methyl-5- morpholin-4-ylpyrazol-3- yl)oxyphenyl]pyridin-3- yl]ethanamine  976

[6-[4-fluoro-2-(2-methyl-5- morpholin-4-ylpyrazo1-3- yl)oxyphenyl]pyridin-3- yl]methanamine  977

2-[2-[4-fluoro-2-(2-methyl-5-pyridin- 2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  978

2-[2-[4-fluoro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  979

2-[2-[4-fluoro-2-(2-methyl-5- pyrrolidin-1-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  980

2-[6-[4-fluoro-2-(2-methyl-5- pyrrolidin-1-ylpyrazol-3- yl)oxyphenyl]pyridin-3- yl]ethanamine  981

2-[2-[4-fluoro-2-(1-propan-2- ylpyrazol-4-yl)oxyphenyl]pyrimidin- 5-yl]ethanamine  982

2-[2-[4-fluoro-2-[1-(2- methylpropyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine  983

2-[2-[4-fluoro-2-(3-methyl-1-propan- 2-ylpyrazol-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  984

2-[2-[4-fluoro-2-(5-methyl-1-propan- 2-ylpyrazol-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine  985

2-[2-[2-[1-(2,2-dimethylpropyl)-3- methylpyrazol-4-yl]oxy-4- fluorophenyl]pyrimidin-5- yl]ethanamine  986

2-[2-[2-[1-(2,2-dimethylpropyl)-5- methylpyrazol-4-yl]oxy-4- fluorophenyl]pyrimidin-5- yl]ethanamine  987

5-[2-[5-(2-aminoethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N-(2,2- difluoroethyl)-N,1-dimethylpyrazole- 3-amine  988

5-[2-[5-(2-aminoethyl)pyridin-2-yl]- 5-fluorophenoxy]-N-(2,2- difluoroethyl)-N,1-dimethylpyrazole- 3-amine  989

5-[2-[5-(2-aminoethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N-(2,2- difluoroethyl)-N-ethyl-1- methylpyrazole-3-amine  990

5-[2-[5-(2-aminoethyl)pyridin-2-yl]- 5-fluorophenoxy]-N-(2,2- difluoroethyl)-N-ethyl-1- methylpyrazole-3-amine  991

5-[2-[5-(2-aminoethyl)pyridin-2-yl]- 5-fluorophenoxy]-N,N-diethyl-1- methylpyrazole-3-amine  992

5-[2-[5-(aminomethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N,N-diethyl-1- methylpyrazole-3-amine  993

5-[2-[5-(aminomethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N-(2,2- difluoroethyl)-N,1-dimethylpyrazole- 3-amine  994

5-[2-[5-(aminomethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N-(2,2- difluoroethyl)-N-ethyl-1 methylpyrazole-3-amine  995

[2-[4-fluoro-2-(2-methyl-5- pyrrolidin-1-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]methanamine  996

[6-[4-fluoro-2-(2-methyl-5- pyrrolidin-1-ylpyrazol-3- yl)oxyphenyl]pyridin-3- yl]methanamine  997

5-[2-[5-(aminomethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N,N,1 trimethylpyrazole-3-amine  998

5-[2-[5-(aminomethyl)pyridin-2-yl]- 5-fluorophenoxy]-N,N,1- trimethylpyrazole-3-amine  999

5-[2-[5-(2-aminoethyl)pyrimidin-2- yl]-5-fluorophenoxy]-N,N,1- trimethylpyrazole-3-amine 1000

5-[2-[5-(2-aminoethyl)pyridin-2-yl]- 5-fluorophenoxy]-N,N,1- trimethylpyrazole-3-amine 1001

2-[6-[4-fluoro-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyridin-3- yl]ethanamine 1002

[2-[4-fluoro-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5- yl]methanamine 1003

[6-[4-fluoro-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyridin-3- yl]methanamine 1004

2-[2-[4-fluoro-2-(1-pyridin-2- ylpyrazol-4-yl)oxyphenyl]pyrimidin- 5-yl]ethanamine 1005

2-[2-[2-[1-(2,2-difluoroethyl)pyrazol- 4-yl]oxy-4-fluorophenyl]pyrimidin-5- yl]ethanamine 1006

2-[6-[4-fluoro-2-(6-morpholin-4- ylpyridazin-4-yl)oxyphenyl]pyridin- 3-yl]ethanamine 1007

[2-[4-fluoro-2-[2-methyl-5-(oxan-4- yl)pyrazol-3-yl]oxyphenyl]pyrimidin- 5-yl]methanamine 1008

[6-[4-fluoro-2-[2-methyl-5-(oxan-4- yl)pyrazol-3-yl]oxyphenyl]pyridin-3- yl]methanamine 1009

2-[2-[4-fluoro-2-[2-methyl-5-(oxan-4- yl)pyrazol-3-yl]oxyphenyl]pyrimidin- 5-yl]ethanamine 1010

2-[6-[4-fluoro-2-[2-methyl-5-(oxan-4- yl)pyrazol-3-yl]oxyphenyl]pyridin-3- yl]ethanamine 1011

[6-[4-fluoro-2-(2-methyl-5-propan-2- ylpyrazol-3-yl)oxyphenyl]pyridin-3- yl]methanamine 1012

[2-[4-fluoro-2-(2-methyl-5-propan-2- ylpyrazol-3-yl)oxyphenyl]pyrimidin- 5-yl]methanamine 1013

2-[2-[4-fluoro-2-(2-methyl-5-propan- 2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]ethanamine 1014

2-[6-[4-fluoro-2-(2-methyl-5-propan- 2-ylpyrazol-3-yl)oxyphenyl]pyridin- 3-yl]ethanamine 1015

[2-[2-(5-cyclopropyl-2- methylpyrazol-3-yl)oxy-4- fluorophenyl]pyrimidin-5- yl]methanamine 1016

[6-[2-(5-cyclopropyl-2- methylpyrazol-3-yl)oxy-4- fluorophenyl]pyridin- 3 - yl]methanamine 1017

2-[2-[2-(5-cyclopropyl-2- methylpyrazol-3-yl)oxy-4- fluorophenyl]pyrimidin-5- yl]ethanamine 1018

2-[6-[2-(5-cyclopropyl-2- methylpyrazol-3-yl)oxy-4- fluorophenyl]pyridin-3-yl]ethanamine 1019

2-[2-[4-fluoro-2-[1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine 1020

2-[2-[4-chloro-2-(1-propan-2- ylpyrazol-4-yl)oxyphenyl]pyrimidin- 5-yl]ethanamine 1021

2-[2-[4-chloro-2-[1-(2- methylpropyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine 1022

2-[2-[4-chloro-2-[1-(2,2- difluoroethyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine 1023

2-[2-[4-chloro-2-[1-(2,2,2- trifluoroethyl)pyrazol-4- yl]oxyphenyl]pyrimidin-5- yl]ethanamine 1024

2-[2-[4-chloro-2-(1-pyridin-2- ylpyrazol-4-yl)oxyphenyl]pyrimidin- 5-yl]ethanamine 1025

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-ethyl-2-methylpyrazole-3- carbonyl)benzonitrile 1026

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-ethyl-2-methylpyrazole-3- carbonyl)benzonitrile 1027

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyrazole- 3-carbonyl)benzonitrile 1028

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyrazole- 3-carbonyl)benzonitrile 1029

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-methyl-5-morpholin-4-ylpyrazole- 3-carbonyl)benzonitrile 1030

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-tert-butyl-2-methylpyrazole-3- carbonyl)benzonitrile 1031

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-tert-butyl-2-methylpyrazole-3- carbonyl)benzonitrile 1032

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-(diethylamino)-2-methylpyrazole- 3-carbonyl]benzonitrile 1033

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(cyclopropylmethyl)-3- methylpyrazole-4- carbonyl]benzonitrile 1034

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(cyclopropylmethyl)-5- methylpyrazole-4- carbonyl]benzonitrile 1035

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [1-(cyclopropylmethyl)-3- methylpyrazole-4- carbonyl]benzonitrile 1036

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [1-(cyclopropylmethyl)-5- methylpyrazole-4- carbonyl]benzonitrile 1037

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (1-pyridin-2-ylpyrazole-4- carbonyl)benzonitrile 1038

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (1-pyridin-2-ylpyrazole-4- carbonyl)benzonitrile 1039

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-(trifluoromethyl)-1,3-thiazole-5- carbonyl]benzonitrile 1040

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidine-4-carbonyl)benzonitrile 1041

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(oxan-4-yl)pyrazole-4- carbonyl]benzonitrile 1042

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridine- 4-carbonyl)benzonitrile 1043

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-(dimethylamino)-2- methylpyrazole-3- carbonyl]benzonitrile 1044

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (1-propan-2-ylpyrazole-4- carbonyl)benzonitrile 1045

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (1-propan-2-ylpyrazole-4- carbonyl)benzonitrile 1046

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(cyclopropylmethyl)pyrazole-4- carbonyl]benzonitrile 1047

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [1-(cyclopropylmethyl)pyrazole-4- carbonyl]benzonitrile 1048

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(1,3-thiazol-2-yl)pyrazole-4- carbonyl]benzonitrile 1049

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridine- 4-carbonyl)benzonitrile 1050

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [1-(1,3-thiazol-2-yl)pyrazole-4- carbonyl]benzonitrile 1051

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(dimethylamino)-2- methylpyrazole-3- carbonyl]benzonitrile 1052

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (1-pyrimidin-2-ylpyrazole-4- carbonyl)benzonitrile 1053

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidine-4-carbonyl)benzonitrile 1054

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (3-methyl-1-propan-2-ylpyrazole-4- carbonyl)benzonitrile 1055

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (1-pyrimidin-4-ylpyrazole-4- carbonyl)benzonitrile 1056

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [1-(oxan-4-yl)pyrazole-4- carbonyl]benzonitrile 1057

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (1-cyclobutylpyrazole-4- carbonyl)benzonitrile 1058

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (1-cyclobutylpyrazole-4- carbonyl)benzonitrile 1059

4-[4-(2-aminoethyl)phenyl]-3-(4- methyl-2-morpholin-4-yl-1,3- thiazole-5-carbonyl)benzonitrile 1060

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [1-(2-methylpropyl)pyrazole-4- carbonyl]benzonitrile 1061

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-(diethylamino)-2-methylpyrazole- 3-carbonyl]benzonitrile 1062

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-piperidin-1-ylpyrazole-3- carbonyl)benzonitrile 1063

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-piperidin-1-ylpyrazole-3- carbonyl)benzonitrile 1064

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (4-methyl-2-morpholin-4-yl-1,3- thiazole-5-carbonyl)benzonitrile 1065

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (4-methyl-2-morpholin-4-yl-1,3- thiazole-5-carbonyl)benzonitrile 1066

4-[5-(aminomethyl)pyridin-2-yl]-3- (4-methyl-2-morpholin-4-yl-1,3- thiazole-5-carbonyl)benzonitrile 1067

4-[5-(aminomethyl)pyridin-2-yl]-3- (5-methyl-2-morpholin-4-yl-1,3- thiazole-4-carbonyl)benzonitrile 1068

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-methyl-2-morpholin-4-yl-1,3- thiazole-4-carbonyl)benzonitrile 1069

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-methyl-2-morpholin-4-yl-1,3- thiazole-4-carbonyl)benzonitrile 1070

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-methyl-2-morpholin-4-yl-1,3- thiazole-4-carbonyl)benzonitrile 1071

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrrolidin-1-ylpyrazole- 3-carbonyl)benzonitrile 1072

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-5-pyrrolidin-1-ylpyrazole- 3-carbonyl)benzonitrile 1073

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [5-[2,2-difluoroethyl(ethyl)amino]-2- methylpyrazole-3- carbonyl]benzonitrile 1074

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [5-[2,2-difluoroethyl(ethyl)amino]-2- methylpyrazole-3- carbonyl]benzonitrile 1075

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-methyl-5-(methylamino)pyrazole- 3-carbonyl]benzonitrile 1076

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (4-methyl-2-morpholin-4-yl-1,3- thiazole-5-carbonyl)benzonitrile 1077

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [2-morpholin-4-yl-4- (trifluoromethyl)-1,3-thiazole-5- carbonyl]benzonitrile 1078

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [2-morpholin-4-yl-4- (trifluoromethyl)-1,3-thiazole-5- carbonyl]benzonitrile 1079

4-[4-(2-aminoethyl)phenyl]-3-(6- morpholin-4-ylpyridazine-4- carbonyl)benzonitrile 1080

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-morpholin-4-yl-4- (trifluoromethyl)-1,3-thiazole-5- carbonyl]benzonitrile 1081

4-[4-(2-aminoethyl)phenyl]-3-(2- morpholin-4-yl-1,3-oxazole-5- carbonyl)benzonitrile 1082

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-morpholin-4-yl-1,3-oxazole-5- carbonyl)benzonitrile 1083

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-morpholin-4-yl-1,3-oxazole-5- carbonyl)benzonitrile 1084

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-morpholin-4-yl-1,3-oxazole-5- carbonyl)benzonitrile 1085

4-[5-(aminomethyl)pyridin-2-yl]-3- (2-morpholin-4-yl-1,3-oxazole-5- carbonyl)benzonitrile 1086

4-[4-(2-aminoethyl)phenyl]-3-(5- morpholin-4-yl-1,3,4-oxadiazole-2- carbonyl)benzonitrile 1087

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-morpholin-4-yl-4- (trifluoromethyl)-1,3-thiazole-5- carbonyl]benzonitrile 1088

4-[4-(2-aminoethyl)phenyl]-3-(5- morpholin-4-yl-1,3,4-thiadiazole-2- carbonyl)benzonitrile 1089

4-[5-(aminomethyl)pyridin-2-yl]-3- (5-morpholin-4-yl-1,3,4-oxadiazole- 2-carbonyl)benzonitrile 1090

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-morpholin-4-yl-1,3,4-oxadiazole- 2-carbonyl)benzonitrile 1091

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-morpholin-4-yl-1,3,4-oxadiazole- 2-carbonyl)benzonitrile 1092

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-morpholin-4-yl-1,3,4-oxadiazole- 2-carbonyl)benzonitrile 1093

4-[5-(aminomethyl)pyridin-2-yl]-3- (5-morpholin-4-yl-1,3,4-thiadiazole- 2-carbonyl)benzonitrile 1094

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (5-morpholin-4-yl-1,3,4-thiadiazole- 2-carbonyl)benzonitrile 1095

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (5-morpholin-4-yl-1,3,4-thiadiazole- 2-carbonyl)benzonitrile 1096

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (5-morpholin-4-yl-1,3,4-thiadiazole- 2-carbonyl)benzonitrile 1097

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(2-methyl-6- morpholin-4-ylpyridin-4- yl)methanone 1098

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-[1-(2,2- difluoroethyl)pyrazol-4-yl]methanone 1099

[2-[5-(aminomethyl)pyrimidin-2-yl]- 5-fluorophenyl]-[1-(2,2- difluoroethyl)pyrazol-4-yl]methanone 1100

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(1-methylpyrazol-4- yl)methanone 1101

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-[1- (cyclopropylmethyl)pyrazol-4- yl]methanone 1102

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(1-propan-2- ylpyrazol-4-yl)methanone 1103

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)methanone 1104

[2-[5-(aminomethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)methanone 1105

[2-[5-(aminomethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(2-methyl-5- morpholin-4-ylpyrazol-3- yl)methanone 1106

[2-[5-(2-aminoethyl)pyridin-2-yl]-5- fluorophenyl]-(2-methyl-5- morpholin-4-ylpyrazol-3- yl)methanone 1107

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(2-methyl-5- morpholin-4-ylpyrazol-3- yl)methanone 1108

[2-[5-(2-aminoethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(1-cyclobutylpyrazol- 4-yl)methanone 1109

[2-[5-(aminomethyl)pyrimidin-2-yl]- 5-fluorophenyl]-(1-cyclobutylpyrazol- 4-yl)methanone 1110

[2-[5-(2-aminoethyl)pyridin-2-yl]-5- fluorophenyl]-(1-cyclobutylpyrazol-4- yl)methanone 1111

4-[4-(2-aminoethyl)phenyl]-3-[(4- phenylimidazol-1- yl)methyl]benzonitrile 1112

4-[4-(2-aminoethyl)phenyl]-3-[(3- phenylpyrazol-1- yl)methyl]benzonitrile 1113

1-[[2-[4-(2-aminoethyl)phenyl]-5- cyanophenyl]methyl]-N-propan-2- ylimidazole-4-carboxamide 1114

1-[[2-[4-(2-aminoethyl)phenyl]-5- cyanophenyl]methyl]-N-(2- methylpropyl)imidazole-4- carboxamide 1115

3-[[2-[4-(2-aminoethyl)phenyl]-5- cyanophenyl]methyl]-N-(2- methylpropyl)imidazole-4- carboxamide 1116

4-[4-(2-aminoethyl)phenyl]-3-[[5- (methoxymethyl)imidazol-1- yl]methyl]benzonitrile 1117

4-[4-(2-aminoethyl)phenyl]-3-[[5-(2- methylpropoxymethyl)imidazol-1- yl]methyl]benzonitrile 1118

4-[4-(2-aminoethyl)phenyl]-3-[[4- (methoxymethyl)imidazol-1- yl]methyl]benzonitrile 1119

4-[4-(2-aminoethyl)phenyl]-3-[[4-(2- methylpropoxymethyl)imidazol-1- yl]methyl]benzonitrile 1120

4-[4-(2-aminoethyl)phenyl]-3-[(2- methyl-4-phenylimidazol-1- yl)methyl]benzonitrile 1121

4-[4-(2-aminoethyl)phenyl]-3-[(2- propylimidazol-1- yl)methyl]benzonitrile 1122

4-[4-(2-aminoethyl)phenyl]-3-[[4- (triazol-1-yl)imidazol-1- yl]methyl]benzonitrile 1123

4-[4-(2-aminoethyl)phenyl]-3-[[4- (tetrazol-1-yl)imidazol-1- yl]methyl]benzonitrile 1124

4-[4-(2-aminoethyl)phenyl]-3-[[4-[4- (trifluoromethyl)phenyl]imidazol-1- yl]methyl]benzonitrile 1125

4-[4-(2-aminoethyl)phenyl]-3-[[2- methyl-4-[4- (trifluoromethyl)phenyl]imidazol-1- yl]methyl]benzonitrile 1126

4-[4-(2-aminoethyl)phenyl]-3-[[2- methyl-4-(propan-2- yloxymethyl)imidazol-1- yl]methyl]benzonitrile 1127

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[(4- phenylimidazol-1 yl)methyl]benzonitrile 1128

4-[4-(2-amino-1- hydroxyethyl)pyrazol-1-yl]-3-[(2- methyl-4-phenylimidazol-1- yl)methyl]benzonitrile 1129

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-[(4- phenylimidazol-1- yl)methyl]benzonitrile 1130

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-[(2-methyl-4- phenylimidazol-1- yl)methyl]benzonitrile 1131

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(4-phenylimidazol-1- yl)methyl]benzonitrile 1132

4-[6-(2-aminoethyl)pyridin-3-yl]-3- [(4-phenylimidazol-1- yl)methyl]benzonitrile 1133

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-[(5- phenylimidazol-1- yl)methyl]benzonitrile 1134

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-phenylimidazol-1- yl)methyl]benzonitrile 1135

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-phenylimidazol-1- yl)methyl]benzonitrile 1136

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[(5- phenylimidazol-1- yl)methyl]benzonitrile 1137

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-methyl-4-phenylimidazol-1- yl)methyl]benzonitrile 1138

4-[5-[(1R)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[(4- phenylimidazol-1- yl)methyl]benzonitrile 1139

4-[5-(2-amino-1- hydroxyethyl)pyridin-2-yl]-3-[(2- methyl-4-phenylimidazol-1- yl)methyl]benzonitrile 1140

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(1-methoxyethyl)-2- methylimidazol-1- yl]methyl]benzonitrile 1141

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[4-(1-methoxyethyl)-2- methylimidazol-1- yl]methyl]benzonitrile 1142

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[4-(1-methoxypropyl)-2- methylimidazol-1- yl]methyl]benzonitrile 1143

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(2-fluorophenyl)imidazol-1- yl]methyl]benzonitrile 1144

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(2-chlorophenyl)imidazol-1- yl]methyl]benzonitrile 1145

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(2-methylphenyl)imidazol-1- yl]methyl]benzonitrile 1146

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(4-methylphenyl)imidazol-1- yl]methyl]benzonitrile 1147

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(4-fluorophenyl)imidazol-1- yl]methyl]benzonitrile 1148

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(3-methylphenyl)imidazol-1- yl]methyl]benzonitrile 1149

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(3-fluorophenyl)imidazol-1- yl]methyl]benzonitrile 1150

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(2-methyl-4-phenylimidazol-1- yl)methyl]benzonitrile 1151

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[2-methyl-4-(2- methylphenyl)imidazol-1- yl]methyl]benzonitrile 1152

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(2-fluorophenyl)-2- methylimidazol-1- yl]methyl]benzonitrile 1153

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[2-methyl-4-(4- methylphenyl)imidazol-1- yl]methyl]benzonitrile 1154

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(4-fluorophenyl)-2- methylimidazol-1- yl]methyl]benzonitrile 1155

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[2-methyl-4-(3- methylphenyl)imidazol-1- yl]methyl]benzonitrile 1156

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(3-fluorophenyl)-2- methylimidazol-1- yl]methyl]benzonitrile 1157

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(2-methyl-4-pyridin-2-ylimidazol-1- yl)methyl]benzonitrile 1158

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(5-methyl-3-phenylpyrazol-1- yl)methyl]benzonitrile 1159

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(3-tert-butyl-5-methylpyrazol-1- yl)methyl]benzonitrile 1160

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(4-pyridin-2-ylimidazol-1- yl)methyl]benzonitrile 1161

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[[4-(3- fluorophenyl)-2-methylimidazol-1- yl]methyl]benzonitrile 1162

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[[4- (3-fluorophenyl)-2-methylimidazol-1- yl]methyl]benzonitrile 1163

4-[5-(aminomethyl)pyridin-2-yl]-3- [[2-methyl-4-(oxan-4-yl)imidazol-1- yl]methyl]benzonitrile 1164

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[2-methyl-4-(oxan-4-yl)imidazol-1- yl]methyl]benzonitrile 1165

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyridin-2-yl]-3-[[2- methyl-4-(oxan-4-yl)imidazol-1- yl]methyl]]benzonitrile 1166

4-[5-[(1S)-2-amino-1- hydroxyethyl]pyrimidin-2-yl]-3-[[2- methyl-4-(oxan-4-yl)imidazol-1- yl]methyl]]benzonitrile 1167

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-phenyltriazol-1- yl)methyl]benzonitrile 1168

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(4-phenyltriazol-1- yl)methyl]benzonitrile 1169

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-phenyltriazol-2- yl)methyl]benzonitrile 1170

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(4-phenyltriazol-2- yl)methyl]benzonitrile 1171

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-methyl-4-propan-2-ylimidazol-1- yl)methyl]benzonitrile 1172

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-4-propan-2-ylimidazol-1- yl)methyl]benzonitrile 1173

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[2-methyl-4- (trifluoromethyl)imidazol-1- yl]methyl]benzonitrile 1174

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[2-methyl-4- (trifluoromethyl)imidazol-1- yl]methyl]benzonitrile 1175

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[2-methyl-4-(pyrrolidin-1- ylmethyl)imidazol-1- yl]methyl]benzonitrile 1176

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[4-(difluoromethyl)-2- methylimidazol-1- yl]methyl]benzonitrile 1177

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[4-[(4-fluoropiperidin-1-yl)methyl]- 2-methylimidazol-1- yl]methyl]benzonitrile 1178

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[4-[(dimethylamino)methyl]-2- methylimidazol-1- yl]methyl]benzonitrile 1179

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[2-methyl-4-(piperidin-1- ylmethyl)imidazol-1- yl]methyl]benzonitrile 1180

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[2-methyl-4-[[4- (trifluoromethyl)piperidin-1- yl]methyl]imidazol-1- yl]methyl]benzonitrile 1181

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[2-methyl-4-[(propan-2- ylamino)methyl]imidazol-1- yl]methyl]benzonitrile 1182

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-phenylimidazol-1- yl)methyl]benzonitrile 1183

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-phenylimidazol-1- yl)methyl]benzonitrile 1184

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[4-(2-methylpropyl)triazol-1- yl]methyl]benzonitrile 1185

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-propan-2-yltriazol-1- yl)methyl]benzonitrile 1186

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-cyclohexyltriazol-1- yl)methyl]benzonitrile 1187

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-cyclopropyltriazol-1- yl)methyl]benzonitrile 1188

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[4-(2-methylpropyl)triazol-1- yl]methyl]benzonitrile 1189

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(4-propan-2-yltriazol-1- yl)methyl]benzonitrile 1190

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(4-cyclohexyltriazol-1- yl)methyl]benzonitrile 1191

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(4-cyclopropyltriazol-1- yl)methyl]benzonitrile 1192

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[4-(5-fluoropyridin-3-yl)-2- methylimidazol-1- yl]methyl]benzonitrile 1193

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[4-(5-fluoropyridin-3-yl)-2- methylimidazol-1- yl]methyl]benzonitrile 1194

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[4-(5-fluoropyridin-3-yl)-2- methylimidazol-1- yl]methyl]benzonitrile 1195

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[1-(2-methylpropyl)pyrazol-4- yl]methyl]benzonitrile 1196

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[1-(2-methylpropyl)pyrazol-4- yl]methyl]benzonitrile 1197

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(1-pyridin-2-ylpyrazol-4- yl)methyl]benzonitrile 1198

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-pyrrolidin-1-ylpyrazol-1- yl)methyl]benzonitrile 1199

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[3-methyl-1-(2- methylpropyl)pyrazol-4- yl]methyl]benzonitrile 1200

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-morpholin-4-ylpyrazol-1- yl)methyl]benzonitrile 1201

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(4-phenylpyrazol-1- yl)methyl]benzonitrile 1202

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(3-methyl-1-pyridin-2-ylpyrazol-4- yl)methyl]benzonitrile 1203

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(3-methyl-1-pyridin-2-ylpyrazol-4- yl)methyl]benzonitrile 1204

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-methyl-6-morpholin-4-ylpyridin- 4-yl)methyl]benzonitrile 1205

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-5-pyridin-2-ylpyrazol-3- yl)methyl]benzonitrile 1206

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[5-(diethylamino)-2-methylpyrazol- 3-yl]methyl]benzonitrile 1207

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[5-(diethylamino)-2-methylpyrazol- 3-yl]methyl]benzonitrile 1208

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[5-(diethylamino)-2-methylpyrazol- 3-yl]methyl]benzonitrile 1209

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [[5-(dimethylamino)-2- methylpyrazol-3- yl]methyl]benzonitrile 1210

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-5-pyrrolidin-1-ylpyrazol- 3-yl)methyl]benzonitrile 1211

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-methyl-5-pyrrolidin-1-ylpyrazol- 3-yl)methyl]benzonitrile 1212

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(2-methyl-5-pyrrolidin-1-ylpyrazol- 3-yl)methyl]benzonitrile 1213

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(2-methyl-5-piperidin-1-ylpyrazol-3- yl)methyl]benzonitrile 1214

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-methyl-5-pyridin-2-ylpyrazol-3- yl)methyl]benzonitrile 1215

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(2-methyl-5-pyridin-2-ylpyrazol-3- yl)methyl]benzonitrile 1216

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [[5-(dimethylamino)-2- methylpyrazol-3- yl]methyl]benzonitrile 1217

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [[5-(dimethylamino)-2- methylpyrazol-3- yl]methyl]benzonitrile 1218

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(2-methyl-5-piperidin-1-ylpyrazol-3- yl)methyl]benzonitrile 1219

4-[5-(2-aminoethyl)pyridin-2-yl]-3- [(2-methyl-5-piperidin-1-ylpyrazol-3- yl)methyl]benzonitrile 1220

2-[2-[4-fluoro-2-[(1-pyridin-2- ylpyrazol-4- yl)methyl]phenyl]pyrimidin-5- yl]ethanamine 1221

2-[6-[4-fluoro-2-[[1-(2- methylpropyl)pyrazol-4- yl]methyl]phenyl]pyridin-3- yl]ethanamine 1222

2-[2-[4-fluoro-2-[[1-(2- methylpropyl)pyrazol-4- yl]methyl]phenyl]pyrimidin-5- yl]ethanamine 1223

[2-[4-fluoro-2-[[1-(2- methylpropyl)pyrazol-4- yl]methyl]phenyl]pyrimidin-5- yl]methanamine 1224

2-[2-[4-fluoro-2-[[3-methyl-1-(2- methylpropyl)pyrazol-4- yl]methyl]phenyl]pyrimidin-5- yl]ethanamine 1225

[2-[4-fluoro-2-[[3-methyl-1-(2- methylpropyl)pyrazol-4- yl]methyl]phenyl]pyrimidin-5- yl]methanamine 1226

4-[4-(2-aminoethyl)phenyl]-3-[1-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)ethyl]benzonitrile 1227

4-[4-(2-aminoethyl)phenyl]-3-[1-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)cyclopropyl]benzonitrile 1228

4-[4-(2-aminoethyl)phenyl]-3-[1-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)ethenyl]benzonitrile 1229

4-[4-(2-aminoethyl)phenyl]-3- [hydroxy-(3-phenyl-1,2-oxazol-5- yl)methyl]benzonitrile 1230

4-[4-(2-aminoethyl)phenyl]-3- [methoxy-(2-phenyl-1,3-thiazol-5- yl)methyl]benzonitrile 1231

4-[4-(2-aminoethyl)phenyl]-3- [methoxy-(3-phenyl-1,2-oxazol-5- yl)methyl]benzonitrile 1232

4-[4-(2-aminoethyl)phenyl]-3- [methoxy-[3-(1,3-thiazol-2-yl)-1,2- oxazol-5-yl]methyl]benzonitrile 1233

4-[5-(aminomethyl)pyridin-2-yl]-3- [(5-tert-butyl-2-methylpyrazol-3-yl)- hydroxymethyl]benzonitrile 1234

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-tert-butyl-2-methylpyrazol-3-yl)- hydroxymethyl]benzonitrile 1235

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-tert-butyl-2-methylpyrazol-3-yl)- hydroxymethyl]benzonitrile 1236

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-tert-butyl-2-methylpyrazol-3-yl)- methoxymethyl]benzonitrile 1237

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-tert-butyl-2-methylpyrazol-3-yl)- (cyanomethoxy)methyl]benzonitrile 1238

4-[4-(2-amino-1- hydroxyethyl)phenyl]-3-(6- morpholin-4-ylpyridazin-4- yl)sulfanylbenzonitrile 1239

4-[4-(2-aminoethyl)phenyl]-3-(6- morpholin-4-ylpyridazin-4- yl)sulfanylbenzonitrile 1240

4-[4-(2-aminoethyl)phenyl]-3-(6- piperidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1241

4-[4-(2-aminoethyl)phenyl]-3-(6- pyrrolidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1242

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)sulfanylbenzonitrile 1243

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1244

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1245

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)sulfanylbenzonitrile 1246

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1247

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1248

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)sulfanylbenzonitrile 1249

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-piperidin-1-ylpyrimidin- 4-yl)sulfanylbenzonitrile 1250

4-[5-(2-aminoethyl)pyridin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyrimidin- 4-yl)sulfanylbenzonitrile 1251

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)sulfanylbenzonitrile 1252

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (2-methyl-6-piperidin-1-ylpyrimidin- 4-yl)sulfanylbenzonitrile 1253

4-[4-(2-aminoethyl)pyrazol-1-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyrimidin- 4-yl)sulfanylbenzonitrile 1254

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4- ylpyrimidin-4-yl)sulfanylbenzonitrile 1255

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-piperidin-1-ylpyrimidin- 4-yl)sulfanylbenzonitrile 1256

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyrimidin- 4-yl)sulfanylbenzonitrile 1257

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-morpholin-4-ylpyridazin-4- yl)sulfanylbenzonitrile 1258

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1259

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1260

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)sulfanylbenzonitrile 1261

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)sulfanylbenzonitrile 1262

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (2-methyl-6-pyrrolidin-1-ylpyrimidin- 4-yl)sulfanylbenzonitrile 1263

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(dimethylamino)-2- methylpyrimidin-4- yl]sulfanylbenzonitrile 1264

4-[5-(aminomethyl)pyridin-2-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1265

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-pyrrolidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1266

4-[5-(aminomethyl)pyridin-2-yl]-3- [6-(dimethylamino)pyridazin-4- yl]sulfanylbenzonitrile 1267

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(dimethylamino)pyridazin-4- yl]sulfanylbenzonitrile 1268

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)sulfanylbenzonitrile 1269

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-piperidin-1-yl-1,3,4-thiadiazol-2- yl)sulfanyl]benzonitrile 1270

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- [(5-piperidin-1-yl-1,3,4-thiadiazol-2- yl)sulfanyl]benzonitrile 1271

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [(5-morpholin-4-yl-1,3,4-thiadiazol- 2-yl)sulfanyl]benzonitrile 1272

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(propan-2-ylamino)pyridazin-4- yl]sulfanylbenzonitrile 1273

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [6-(2-methylpropylamino)pyridazin- 4-yl]sulfanylbenzonitrile 1274

5-[2-[5-(2-aminoethyl)pyrimidin-2- yl]-5-cyanophenyl]sulfanyl-2-phenyl- 1,3-thiazole-4-carbonitrile 1275

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-phenylpyridazin-4- yl)sulfinylbenzonitrile 1276

4-[5-(2-aminoethyl)pyrimidin-2-yl]-3- (6-piperidin-1-ylpyridazin-4- yl)sulfinylbenzonitrile 1277

5-[5-(2-aminoethyl)pyridin-2-yl]-4- (2-methyl-5-phenylpyrazol-3- yl)oxypyridine-2-carbonitrile 1278

5-[5-(aminomethyl)pyridin-2-yl]-4- (2-methyl-5-phenylpyrazol-3- yl)oxypyridine-2-carbonitrile 1279

5-[5-(2-aminoethyl)pyridin-2-yl]-6- (2-methyl-5-phenylpyrazol-3- yl)oxypyridine-2-carbonitrile 1280

5-[5-(2-aminoethyl)pyridin-2-yl]-6- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxypyridine-2-carbonitrile 1281

5-[5-(2-aminoethyl)pyrimidin-2-yl]-6- (5-cyclopropyl-2-methylpyrazol-3- yl)oxypyridine-2-carbonitrile 1282

5-[5-(2-aminoethyl)pyridin-2-yl]-6- (2-methyl-6-pyrrolidin-1-ylpyridin-4- yl)oxypyridine-2-carbonitrile 1283

5-[5-(aminomethyl)pyrimidin-2-yl]-6- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxypyridine-2-carbonitrile 1284

5-[5-(2-aminoethyl)pyridin-2-yl]-6- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxypyridine-2-carbonitrile 1285

5-[5-(aminomethyl)pyrimidin-2-yl]-6- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxypyridine-2-carbonitrile 1286

5-[5-(aminomethyl)pyrimidin-2-yl]-6- (2-methyl-6-pyridin-2-ylpyridin-4- yl)oxypyridine-2-carbonitrile 1287

6-[5-(aminomethyl)pyrimidin-2-yl]-5- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxypyridine-3-carbonitrile 1288

6-[4-(aminomethyl)phenyl]-5-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxypyridine-3-carbonitrile 1289

6-[5-(aminomethyl)pyridin-2-yl]-5- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxypyridine-3-carbonitrile 1290

2-[6-[6-chloro-4-(2-methyl-5- phenylpyrazol-3-yl)oxypyridin-3- yl]pyridin-3-yl]ethanamine 1291

[6-[6-chloro-4-(2-methyl-5- phenylpyrazol-3-yl)oxypyridin-3- yl]pyridin-3-yl]methanamine 1292

2-[6-[6-chloro-2-(2-methyl-5- phenylpyrazol-3-yl)oxypyridin-3- yl]pyridin-3-yl]ethanamine 1293

[6-[6-chloro-2-(2-methyl-5- phenylpyrazol-3-yl)oxypyridin-3- yl]pyridin-3-yl]methanamine 1294

4-[6-(2-amino-1,1- difluoroethyl)pyridin-3-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile 1295

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1296

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1297

4-(6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-2-yl)-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1298

4-[5-(aminomethyl)pyrimidin-2-yl]-3- (6-methyl-2-morpholin-4- ylpyrimidin-4-yl)oxybenzonitrile 1299

4-[5-[(1R)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1300

4-[5-[(1S)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1301

4-[5-[(1R)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1302

4-[5-[(1S)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1303

4-(2-aminoquinazolin-8-yl)-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1304

4-[5-(aminomethyl)-6-methylpyridin- 2-yl]-3-(2-methyl-6-morpholin-4- ylpyridin-4-yl)oxybenzonitrile 1305

4-[5-(aminomethyl)-6- methoxypyridin-2-yl]-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1306

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-methyl-5-[(3S)-oxolan-3- yl]pyrazol-3-yl]oxybenzonitrile 1307

4-[5-(methylamino)pyridin-2-yl]-3- (2-methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1308

4-[5-(aminomethyl)pyrimidin-2-yl]-3- [2-methyl-5-[(3S)-oxolan-3- yl]pyrazol-3-yl]oxybenzonitrile 1309

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-methyl-5-(1-methylpyrazol-4- yl)pyrazol-3-yl]oxybenzonitrile 1310

4-[5-(aminomethyl)-6- methoxypyridin-2-yl]-3-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1311

2-[2-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine 1312

4-[5-(2-amino-1,1- difluoroethyl)pyridin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1313

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile 1314

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile 1315

[2-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyrimidin-5- yl]methanamine 1316

4-[5-(aminomethyl)-4-chloropyridin- 2-yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile 1317

4-[5-(aminomethyl)pyrldin-2-yl]-3- [2-methyl-5-[(2R)-oxolan-2- yl]pyrazol-3-yl]oxybenzonitrile 1318

4-[5-(2-amino-1,1- difluoroethyl)pyrimidin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1319

4-[5-(2-amino-1,1- difluoroethyl)pyrimidin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1320

2-[4-[5-chloro-3-(2-methyl-5-pyridin- 2-ylpyrazol-3-yl)oxypyridin-2- yl]phenyl]ethanamine 1321

[6-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3- yl]methanamine 1322

2-[2-[4-chloro-2-(2-methyl-5-pyridin- 2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]ethanamine 1323

[2-[4-chloro-2-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxyphenyl]pyrimidin- 5-yl]methanamine 1324

(2S)-2-[2-[4-chloro-2-(2-methyl-5- pyridin-2-ylpyrazol-3 yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1325

(2R)-2-[2-[4-chloro-2-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1326

4-[6-(aminomethyl)pyridazin-3-yl]-3- (2-methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1327

4-[5-[(1R)-2-amino-1-hydroxyethyl]- 4-methoxypyrimidin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1328

4-[5-[(1S)-2-amino-1-hydroxyethyl]- 4-methoxypyrimidin-2-yl]-3-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1329

2-[4-[6-chloro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxypyridin-3- yl]phenyl]ethanamine 1330

4-[5-(aminomethyl)pyridin-2-yl]-3- [2-methyl-5-[(3R)-oxan-3-yl]pyrazol- 3-yl]oxybenzonitrile 1331

6-[4-(2-aminoethyl)phenyl]-5-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxypyridine-3-carbonitrile 1332

2-[4-[6-chloro-4-(2-methyl-5-pyridin- 2-ylpyrazol-3-yl)oxypyridin-3- yl]phenyl]ethanamine 1333

4-[3-(aminomethyl)-6-chloropyridin- 2-yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile 1334

4-[5-(aminomethyl)-6-chloropyridin- 2-yl]-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxybenzonitrile 1335

(2S)-2-fluoro-2-[2-[4-fluoro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]ethanamine 1336

(2R)-2-[2-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1337

(2S)-2-[2-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1338

(2S)-2-[6-[4-chloro-2-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-2- fluoroethanamine 1339

(2R)-2-[6-[4-chloro-2-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-2- fluoroethanamine 1340

[6-[4-chloro-2-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxyphenyl]pyridin-3- yl]methanamine 1341

[2-[4-fluoro-2-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxyphenyl]pyrimidin- 5-yl]methanamine 1342

(2R)-2-fluoro-2-[2-[4-fluoro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]ethanamine 1343

[6-[5-chloro-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxypyridin-2- yl]pyridin-3-yl]methanamine 1344

(2S)-2-[2-[4-chloro-2-[2-methyl-5- [(3R)-oxolan-3-yl]pyrazol-3- yl]oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1345

[6-[4-chloro-2-[2-methyl-5-[(3R)- oxolan-3-yl]pyrazol-3- yl]oxyphenyl]pyridin-3- yl]methanamine 1346

[6-[4-chloro-2-(5-cyclopropyl-2- methylpyrazol-3- yl)oxyphenyl]pyridin-3- yl]methanamine 1347

(2S)-2-[2-[4-chloro-2-(5-cyclopropyl- 2-methylpyrazol-3- yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1348

(2R)-2-[2-[4-chloro-2-(5-cyclopropyl- 2-methylpyrazol-3- yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1349

(1S)-2-amino-1-[2-[4-chloro-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyrimidin-5-yl]ethanol 1350

(1R)-2-amino-1-[2-[4-chloro-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyrimidin-5-yl]ethanol 1351

[2-[5-chloro-3-(2-methyl-5-pyridin-2- ylpyrazol-3-yl)oxypyridin-2- yl]pyrimidin-5-yl]methanamine 1352

(2R)-2-[2-[4-chloro-2-[2-methyl-5- [(3R)-oxolan-3-yl]pyrazol-3- yl]oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1353

(2R)-2-[6-[5-chloro-3-(2-methyl-5- pyridin-2-ylpyrazol-3-yl)oxypyridin- 2-yl]pyridin-3-yl]-2-fluoroethanamme 1354

(2S)-2-[6-[5-chloro-3-(2-methyl-5- pyridin-2-ylpyrazol-3-yl)oxypyridin- 2-yl]pyridin-3-yl]-2-fluoroethanamine 1355

[2-[4-chloro-2-(5-cyclopropyl-2- methylpyrazol-3- yl)oxyphenyl]pyrimidin-5- yl]methanamine 1356

[2-[4-chloro-2-[2-methyl-5-[(3S)- oxolan-3-yl]pyrazol-3- yl]oxyphenyl]pyrimidin-5- yl]methanamine 1357

(1R)-2-amino-1-[2-[4-chloro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5-yl]ethanol 1358

(1S)-2-amino-1-[2-[4-chloro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5-yl]ethanol 1359

(2S)-2-[2-[4-chloro-2-[2-methyl-5- (oxan-4-yl)pyrazol-3- yl]oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1360

(2R)-2-[2-[4-chloro-2-[2-methyl-5- (oxan-4-yl)pyrazol-3- yl]oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1361

[6-[4-chloro-2-[2-methyl-5-(oxan-4- yl)pyrazol-3-yl]oxyphenyl]pyridin-3- yl]methanamine 1362

[2-[4-chloro-2-[2-methyl-5-(oxan-4- yl)pyrazol-3-yl]oxyphenyl]pyrimidin- 5-yl]methanamine 1363

(2R)-2-amino-2-[6-[4-chloro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]ethanol 1364

[2-[4-chloro-2-[(2-methyl-5-phenyl 1,2,4-triazol-3- yl)oxy]phenyl]pyrimidin-5- yl]methanamine 1365

2-[2-[4-chloro-2-[(2-methyl-5-phenyl- 1,2,4-triazol-3- yl)oxy]phenyl]pyrimidin-5- yl]ethanamine 1366

4-[5-[(1R)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile 1367

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(5- cyclopropyl-2-methylpyrazol-3- yl)oxybenzonitrile 1368

4-[5-[(1R)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile 1369

4-[5-[(1S)-2-amino-1- fluoroethyl]pyridin-2-yl]-3-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile 1370

(2R)-2-[6-[5-chloro-3-(5-cyclopropyl- 2-methylpyrazol-3-yl)oxypyridin-2- yl]pyridin-3-yl]-2-fluoroethanamine 1371

(2S)-2-[6-[5-chloro-3-(5-cyclopropyl- 2-methylpyrazol-3-yl)oxypyridin-2- yl]pyridin-3-yl]-2-fluoroethanamine 1372

(2R)-2-[6-[5-chloro-3-[2-methyl-5- (oxan-4-yl)pyrazol-3-yl]oxypyridin-2- yl]pyridin-3-yl]-2-fluoroethanamine 1373

(2S)-2-[6-[5-chloro-3-[2-methyl-5- (oxan-4-yl)pyrazol-3-yl]oxypyridin-2- yl]pyridin-3-yl]-2-fluoroethanamine 1374

(2R)-2-[2-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1375

(2S)-2-[2-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5-yl]-2- fluoroethanamine 1376

(1R)-2-amino-1-[2-[4-chloro-2-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5-yl]ethanol 1377

(1S)-2-amino-1-[2-[4-chloro-2-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5-yl]ethanol 1378

2-[2-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine 1379

(1S)-1-[6-[4-chloro-2-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]-2,2,2- trifluoroethanamine 1380

(1R)-1-[6-[4-chloro-2-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3- yl]ethanamine 1381

(2S)-2-[2-[2-(5-cyclopropyl-2- methylpyrazol-3-yl)oxy-4- fluorophenyl]pyrimidin-5-yl]-2- fluoroethanamine 1382

(2R)-2-[2-[2-(5-cyclopropyl-2- methylpyrazol-3-yl)oxy-4- fluorophenyl]pyrimidin-5-yl]-2- fluoroethanamine 1383

(1S)-2-amino-1-[2-[2-(5-cyclopropyl- 2-methylpyrazol-3-yl)oxy-4- fluorophenyl]pyrimidin-5-yl]ethanol 1384

(1R)-2-amino-1-[2-[2-(5-cyclopropyl- 2-methylpyrazol-3-yl)oxy-4- fluorophenyl]pyrimidin-5-yl]ethanol 1385

2-[2-[5-chloro-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxypyridin-2-yl]pyrimidin-5- yl]ethanamine 1386

(2S)-2-[6-[4-chloro-2-[2-methyl-5- (oxan-4-yl)pyrazol-3- yl]oxyphenyl]pyridin-3-yl]-2- fluoroethanamine 1387

(2R)-2-[6-[4-chloro-2-[2-methyl-5- (oxan-4-yl)pyrazol-3- yl]oxyphenyl]pyridin-3-yl]-2- fluoroethanamine 1388

(1S)-2-amino-1-[2-[4-chloro-2-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxyphenyl]pyrimidin-5-yl]ethanol 1389

(1R)-2-amino-1-[2-[4-chloro-2-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxyphenyl]pyrimidin-5-yl]ethanol 1390

2-[2-[4-chloro-2-[2-methyl-5-(oxan- 4-yl)pyrazol-3- yl]oxyphenyl]pyrimidin-5- yl]ethanamine 1391

(2S)-2-amino-2-[2-[4-chloro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyrimidin-5-yl]ethanol 1392

4-(6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl)-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxybenzonitrile 1393

4-(6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-2-yl)-3-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxybenzonitrile 1394

(2R)-2-[6-[4-chloro-2-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]-2- fluoroethanamine 1395

(1R)-2-amino-1-[6-[4-chloro-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]ethanol 1396

(1S)-2-amino-1-[6-[4-chloro-2-(2- methyl-6-morpholin-4-ylpyridin-4- yl)oxyphenyl]pyridin-3-yl]ethanol 1397

(2R)-2-[6-[5-chloro-3-(2-methyl-6- morpholin-4-ylpyridin-4 yl)oxypyridin-2-yl]pyridin-3-yl]-2- fluoroethanamine 1398

(2S)-2-[6-[5-chloro-3-(2-methyl-6- morpholin-4-ylpyridin-4- yl)oxypyridin-2-yl]pyridin-3-yl-2- fluoroethanamine 1399

2-[6-[5-chloro-3-[2-methyl-5-(oxan- 4-yl)pyrazol-3-yl]oxypyridin-2- yl]pyridin-3-yl]-2,2- difluoroethanamine 1400

4-[5-(2-amino-1,1- difluoroethyl)pyridin-2-yl]-3-[2- methyl-5-(oxan-4-yl)pyrazol-3- yl]oxybenzonitrile 1401

(1R)-2-amino-1-[6-[4-chloro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]ethanol 1402

(1S)-2-amino-1-6-[4-chloro-2-(2- methyl-5-pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3-yl]ethanol 1403

4-[5-[(1S)-2-amino-1- fluoroethyl]pyrimidin-2-yl]-3-(2- methyl-6-morpholin-4-ylpyrimidin-4- yl)oxybenzonitrile 1404

[6-[4-chloro-2-fluoro-6-(2-methyl-5- pyridin-2-ylpyrazol-3- yl)oxyphenyl]pyridin-3- yl]methanamine 1405

2-[2-[4-chloro-2-(2,5-dimethyl-6- morpholin-4-ylpyrimidin-4- yl)oxyphenyl]pyrimidin-5- yl]ethanamine

Among these, preferable compounds are those of compound number 2, 6, 7, 9, 11, 17, 21, 25, 26, 30, 32, 33, 46, 50, 62, 65, 66, 69, 70, 82, 93, 100, 101, 112, 113, 115, 120, 130, 133, 137, 138, 149, 150, 153, 157, 159-162, 164, 170-177, 179, 180, 182, 183, 185-187, 197-199, 202, 204-206, 211-213, 215, 225-233, 237, 238, 241, 246-250, 253, 254, 258, 260-262, 264, 266, 267, 272-278, 285, 287-289, 293-296, 299, 301, 306, 310, 312-315, 317-321, 324-329, 333-338, 341, 344, 346, 348, 360-367, 370-376, 378, 379, 381-384, 388, 390-394, 396, 398, 399, 401-407, 413, 426, 429, 430, 432, 434, 439-441, 444-448, 454, 458, 459, 461, 467, 469-471, 477, 482-485, 493, 496, 498-503, 505-510, 517, 521, 522, 525-527, 529-532, 536, 541-544, 550, 562, 575, 587, 592, 599, 604, 609, 610, 619, 621-629, 634, 637, 642, 644, 651, 652, 655-657, 668, 670-672, 691, 695-697, 701, 702, 704, 706, 708, 711, 714, 715, 718, 724, 734, 735, 737, 742, 743, 748, 754, 758-760, 765, 767-770, 772-775, 786, 787, 795, 799, 801-803, 808-812, 822, 823, 826-828, 832-835, 842, 848-850, 854, 856, 857, 859-861, 866, 872-878, 900, 903-910, 912-916, 932, 935, 937, 945, 948-953, 955, 957, 958, 963, 966, 968, 969, 972, 975, 977-980, 983, 985, 987-992, 996, 1000, 1001, 1010-1014, 1017, 1018, 1025-1033, 1035, 1037, 1042-1049, 1051, 1054, 1057-1063, 1065, 1066, 1071-1080, 1086, 1087, 1097, 1106, 1107, 1110, 1120, 1129-1131, 1135, 1137, 1143-1145, 1147-1156, 1167, 1173, 1184-1187, 1195, 1199, 1202, 1203, 1205-1208, 1210-1212, 1214, 1215, 1217-1219, 1233, 1234, 1237, 1239-1241, 1243, 1244, 1249, 1255, 1258, 1259, 1279, 1280, 1295, 1296, 1299-1302, 1304, 1306, 1312, 1316, 1317, 1322-1325, 1330, 1334, 1335, 1337-1340, 1346, 1348, 1350, 1354, 1357, 1360, 1361, 1366-1369, 1371, 1373, 1380, 1387, 1395, 1398 and 1404, more preferably those of compound number 173, 175, 176, 182, 185, 199, 202, 228-230, 237, 250, 254, 258, 260-262, 264, 272, 274, 275, 277, 285, 288, 289, 293, 295, 299, 310, 317, 319, 324-329, 361-364, 367, 371, 390, 391, 393, 394, 402, 439, 440, 444, 445, 447, 448, 454, 459, 461, 470, 471, 541-543, 592, 599, 609, 621-623, 652, 655-658, 671, 672, 697, 706, 754, 758, 769, 770, 773, 775, 786, 787, 795, 801, 802, 810, 811, 812, 826, 827, 832, 833, 835, 842, 849, 856, 857, 859, 860, 866, 874, 875, 877, 907, 912, 937, 948, 953, 955, 958, 963, 966, 972, 975, 977, 979, 980, 987-991, 1000, 1010, 1012-1014, 1018, 1025-1032, 1037, 1042, 1043, 1051, 1061-1063, 1071-1074.

<General Synthesis Method>

The compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof (hereinafter, these are collectively referred to as the compound of the present invention) can be synthesized by a combination of known methods in the art including the synthesis methods described below. Reagents or solvents described as conditions in the chemical formula are merely examples as described in the description. Each substituent may be protected with a suitable protecting group, if necessary, and may be protected or deprotected at an appropriate step. As a suitable protecting group and a removal method of the protecting group, a protecting group for each substituent and a known method, widely used in this field, can be adopted, and are described, for example, in PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley&Sons, Inc. Further, the intermediate produced in the following synthesis method may be isolated and purified by a method such as column chromatography, recrystallization, or distillation, or may be used in the next step without isolation.

Typical synthesis methods of the compound of the present invention represented by the general formula (I) will be described below. The synthesis method of the compound of the present invention is not limited to these. The symbols in each formula are defined in the formula (I).

The compound of the present invention can be produced by several synthesis methods. Hereinafter, a typical synthesis method will be described for each structure of L¹ of the formula (I).

When L¹ in the formula (I) is —NR¹²— in the compound of the present invention, the synthesis can be performed by the method, for example as shown in the following reaction scheme, of constructing a biaryl structure with Ar² ring and then bonding with Ar¹ ring. That is, (A-I) is converted to a boronic acid ester (A-II), then converted to (A-III) by a Suzuki-Miyaura coupling reaction, and then (A-IV) is obtained by a Buchwald-Hartwig amination reaction. The target compound can be synthesized by deprotecting this compound. The target compound can be also synthesized by modifying the amino group after deprotection.

In the following reaction scheme, PG is a protecting group for the amino group (the same applies hereinafter).

Step 1: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. As the base to be used, potassium acetate or the like is preferable. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 3: Tris(dibenzylideneacetone)dipalladium, palladium acetate or the like is preferable as the palladium catalyst. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl or the like is preferable as the ligand. The base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like, potassium tert-butoxide, sodium tert-butoxide and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 150° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 5: The reaction can be performed using an alkyl halide or the like as a reagent having a leaving group. The base includes organic bases such as triethylamine, N,N-diisopropylethylamine, and the like, and inorganic bases such as potassium carbonate, cesium carbonate, and the like. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 120° C., and particularly preferable from 0° C. to room temperature. When X¹, X² and X³ in the formula (I) are CH, the synthesis is performed in the above reaction scheme, while even the compound wherein at least one of X¹, X² and X³ is N or CY (wherein Y is a halogen atom or a methyl group) can be synthesized in the same method.

When L¹ in the formula (I) is —NR¹²— in the compound of the present invention, synthesis can be performed by the method, for example as shown in the following reaction scheme, of reacting with Ar¹ ring having an amino group and constructing the L¹ linker moiety, and then forming a biaryl bond with Ar² ring.

Step 1: Tris(dibenzylideneacetone)dipalladium, palladium acetate or the like is preferable as the palladium catalyst. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl or the like is preferable as the ligand. The base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like, potassium tert-butoxide, sodium tert-butoxide and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 150° C.

Step 2: Bis(pinacolato)diboron is preferable as the borylation reagent and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used include potassium acetate and the like. Here, the solvent is not particularly limited, and include, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: A strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the reagent, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L¹ in the formula (I) is —O— in the compound of the present invention, synthesis can be performed by using the following synthesis methods.

For example, the synthesis can be performed by the method shown in the following reaction scheme. That is, by obtaining (C-II) bonding with Ar¹ ring via an oxygen atom by nucleophilic aromatic substitution reaction, converting (C-II) into a boron compound, a tin compound, or the like, and by performing the cross-coupling reaction with the corresponding Ar² ring compound, the biaryl form (C-IV) can be synthesized. After that, if the amino group is protected, the deprotection thereof can be performed, and if necessary, the target compound can be synthesized by modification of a free amino group. On the other hand, (C-II) can be directly used to perform cross-coupling reaction or the like with Ar² ring compounds having suitable reactive substituents without an operation of step 2. Further, substituent R³ can be converted at an appropriate timing in the following reaction scheme by methods known to those skilled in the art, depending on a target structure.

Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.

Step 2: The borylation reagent to be used includes, for example, bis(pinacolato)diboron and the like, and the tin reagent includes, for example, hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base for borylation. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 3: Tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine or ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 5: Alkyl halide or the like can be used for the reaction as a reaction reagent having a leaving group. The base includes, for example, organic bases such as triethylamine, N,N-diisopropylethylamine and the like, and inorganic bases such as potassium carbonate, cesium carbonate and the like. Tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 120° C.

When L¹ in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized using the intermediate pyrazole (D-I) as shown in the following reaction scheme. That is, after reacting (D-I) with a reagent having a leaving group and modifying the amino group to obtain (D-II), the target compound can be synthesized by the same method as described above.

(Wherein, R^(D1) and R^(D2) are substituents that form —NR^(D1)R^(D2) to satisfy R³ in the formula (I).)

Step 1: Reaction reagent having a leaving group includes, for example, alkyl halides and alkyl triflate and the like. Organic bases such as triethylamine and N,N-diisopropylethylamine, inorganic bases such as potassium carbonate and cesium carbonate or the like is preferable as the base. If necessary, an additive such as potassium iodide may be added. 1,4-Dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or the like is preferable as the solvent. The reaction temperature is preferably from room temperature to 150° C., and particularly preferably from 50° C. to 120° C.

Step 2: The borylation reagent includes, for example, bis(pinacolato)diboron and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized, as shown in the following reaction scheme, by constructing a biaryl bond with Ar² ring, then converting the amino group in (E-III) to a bromine atom, and introducing R³ substituent by, for example, cross-coupling reaction.

Step 1: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 3: Isoamyl nitrite is preferable as the reagent to be used, and copper bromide or the like is preferable as the bromination reagent. Preferred solvents include acetonitrile, toluene, and the like. The reaction temperature is preferably from 0° C. to 50° C.

Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized, as shown in the following reaction scheme, by performing an aromatic nucleophilic substitution reaction using a raw material (F-I) having a nitro group, then converting the functional group of the nitro group, followed by a biaryl bond formation with Ar² ring.

Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 100° C.

Step 2: Iron, zinc, or the like is preferable as the metal reagent to be used, and is preferably used in combination with a reagent such as ammonium chloride, acetic acid, or the like. Preferred solvents include organic solvents such as ethanol, methanol, tetrahydrofuran, and the like, mixed solvents obtained by adding water thereto, and the like. The reaction temperature is preferably from room temperature to 100° C.

Step 3: Isoamyl nitrite is preferable as the reagent to be used, and copper bromide or the like is preferable as the bromination reagent. Preferred solvents include acetonitrile, toluene, and the like. The reaction temperature is preferably from 0° C. to 50° C.

Step 4: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 5: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized, using the intermediate pyrazole (G-IV) obtained through the cyclization reaction, as shown in the following reaction scheme. That is, after reacting a reagent having a leaving group with pyrazole (G-IV) obtained in three steps from the starting material (G-1) to introduce R³ substituent, the target compound can be synthesized by the same method as described above.

Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 100° C.

Step 2: This reaction is preferably performed without solvent. The reaction temperature is preferably from 50° C. to 100° C.

Step 3: The reaction is performed using hydrazine monohydrate as a reagent. Acetic acid or the like is preferable as the solvent. The reaction temperature is preferably from 70° C. to 120° C.

Step 4: The reaction reagent having a leaving group includes, for example, alkyl halides, aryl halides, and the like. Organic bases such as triethylamine and N,N-diisopropylethylamine, and the like, inorganic bases such as potassium carbonate and cesium carbonate, and the like are preferable as the base. Here, the solvent is not particularly limited and includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 150° C.

Step 5: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 6: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 7: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —O— in the compound of the present invention, an aromatic nucleophilic substitution reaction or the like can be also performed using a substrate having a leaving group in Ar¹ ring as shown in the following reaction scheme. (H-IV) can be synthesized by reacting (H-II) directly with Ar² ring compounds having suitable reactive substituents without an operation of step 2. Substituent R³ (e.g., a halogen atom) can be converted to a target structure at an appropriate timing in the following reaction scheme by a method known to those skilled in the art, depending on a target structure.

Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.

Step 2: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 5: The reaction reagent having a leaving group includes, for example, alkyl halides and aryl triflate, and the like. The base includes, for example, organic bases such as triethylamine, N,N-diisopropylethylamine and the like, and inorganic bases such as potassium carbonate, cesium carbonate and the like. Tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 120° C.

When L¹ in the formula (I) is —O— in the compound of the present invention, the target compound can be synthesized by modifying the compound (I-I) having an alcohol as shown in the following reaction scheme.

(Wherein, R¹ is a substituent which forms —OR¹ to satisfy R²¹ in the formula (I).)

Step 1: The reaction reagent having a leaving group includes, for example, alkyl halides and alkyl triflate and the like. Sodium hydride, potassium carbonate, cesium carbonate or the like is preferable as the base. Here, the solvent is not particularly limited and includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 120° C.

Step 2: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate and the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L¹ in the formula (I) is —O— in the compound of the present invention, after converting the alcohol in (J-I) to a leaving group to introduce an alkoxy group as shown in the following reaction scheme, the target compound can also be synthesized by the same method as described above.

(Wherein,

Ms is a methanesulfonyl group; R^(J) is a substituent which forms —OR^(J) to satisfy R²¹ in the formula (I).)

Step 1: As the mesylation reagent, methanesulfonyl chloride can be used to perform the reaction. Triethylamine, potassium carbonate, cesium carbonate or the like is preferable as the base. The solvent is not particularly limited in this reaction and includes, for example, organic solvents such as tetrahydrofuran, dichloromethane, and the like. This reaction is performed preferably at 0° C. to 60° C., and particularly preferably at 0° C. to room temperature.

Step 2: An alcohol (R^(J)—OH) corresponding to the target compound can be used to perform the reaction. As preferred bases, inorganic bases such as sodium hydride, potassium carbonate, cesium carbonate, and the like can be used. The solvent in this reaction includes, for example, organic solvents such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and the like, or a mixed solvent thereof. This reaction is performed preferably at room temperature to 150° C., and particularly preferably at room temperature to 100° C.

Step 3: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L¹ in the formula (I) is —O— in the compound of the present invention, after introducing the target substituent via tosylhydrazone (K-II) as described in the following reaction scheme, synthesis can be performed by the same method as described above.

(Wherein,

Ts is a p-toluenesulfonyl group; R^(K) is a C₁₋₃ alkoxy-C₁₋₃ alkyl group, a hydroxy(C₁₋₆ alkyl) group, a hydroxycarbonyl-(C₁₋₃ alkyl) group, a (C₁₋₃ alkoxy)carbonyl-(C₁₋₃ alkyl) group, or a phenyl group optionally substituted with 1 to 3 halogen atoms.)

Step 1: Tosylhydrazine is used as a reagent in this reaction. Preferred solvents include toluene, methanol, ethanol, and the like. The reaction temperature is preferably from room temperature to 120° C., and particularly preferably from 50° C. to 120° C.

Step 2: Potassium carbonate, cesium carbonate, cesium fluoride or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane and the like. The reaction temperature is preferably from room temperature to 150° C., and particularly preferably from 80° C. to 120° C.

Step 3: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L¹ in the formula (I) is —O— in the compound of the present invention, synthesis can be performed also by a method described in the following reaction scheme. That is, the target compound can be synthesized by the following steps: the raw material (L-I) is reacted with paramethoxybenzyl alcohol to obtain compound (L-II); subsequently, the biaryl compound (L-IV) is obtained through functional group conversion of the bromine atom in (L-II), and then the PMB group is deprotected to lead to phenol (L-V); after linking this phenol (L-V) with Ar¹ compound having a reactive substituent by an appropriate reaction, an amino group is deprotected.

Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 100° C.

Step 2: Bis(pinacolato)diboron is preferable as the borylation reagent to be used, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: As a removal method of the paramethoxybenzyl group, a known method can be adopted. For example, strong acids include such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, and the solvent is not particularly limited and includes, for example, tetrahydrofuran, 1,4-dioxane, dichloromethane and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 5: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.

Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —O— in the compound of the present invention, synthesis can be performed also by a method described in the following reaction scheme. That is, the target compound can be synthesized by the following steps: 2,4-dihydroxy-6-methylpyridine is reacted with the raw material (M-I) to obtain compound (M-II); subsequently, (M-II) is triflated, and then the target R³ substituents is introduced thereto to give (M-IV); subsequently, the biaryl compound (M-VI) is obtained through functional group conversion of the bromine atom in (M-IV), and then the amino group is deprotected.

Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 160° C.

Step 2: The triflation agent to be used includes trifluoromethanesulfonic anhydride (Tf₂O) and the like, and pyridine, triethylamine, N,N-diisopropylethylamine or the like is preferable as the base. Preferred solvents include tetrahydrofuran, dichloromethane, 1,2-dichloroethane and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 3: As a method for introducing R³ substituent, a known method commonly used in the art can be adopted. For example, in the case of introducing R³ substituent using boronic acid derivatives, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Further, for example, in the case of reacting with an alcohol or an amine corresponding to R³ substituent, preferred base includes, for example, organic bases such as triethylamine and N,N-diisopropylethylamine, an inorganic base such as potassium carbonate and cesium carbonate and the like. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.

Step 4: Bis(pinacolato)diboron is preferable as the borylation reagent to be used, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used includes potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 5: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CO— in the compound of the present invention, the synthesis can be performed by using the following synthesis methods.

For example, the synthesis can be performed by the method shown in the following reaction scheme. That is, an Ar¹ ring compound having an aldehyde is reacted with an anionic reagent prepared from the compound (N-I) to synthesize a corresponding alcohol (N-II), which is further oxidized to give a ketone (N-III). Subsequently, a biaryl bond can be formed to synthesize (N-V). Further, R³ substituent can be converted at an appropriate timing in the following reaction scheme by a method known to those skilled in the art, depending on a target structure.

Step 1: The reagent for preparing an anion by reacting with (N-I) includes, for example, n-butyllithium, isopropylmagnesium chloride-lithium chloride complex solution, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from −78° C. to 50° C., and particularly preferably from −40° C. to room temperature.

Step 2: Dess-Martin periodinane, 2-iodoxybenzoic acid, pyridinium chlorochromate or the like is preferable as the oxidizing agent to be used. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 3: The borylation reagent to be used includes bis(pinacolato)diboron and the like, and the tin reagent includes hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CO— in the compound of the present invention, the target compound can be synthesized also by utilizing the intermediate pyrazole (O-II) as shown in the following reaction scheme. That is, after the amino group in (O-II) obtained by reducing (O-I) was modified with a reagent having a leaving group to obtain (O-III), the target compound can be synthesized by the same method as described above.

(Wherein, R^(O1), R^(O2) are substituents that form —NR^(O1)R^(O2) which may be included in R³ of formula (I).)

Step 1: Iron, zinc or the like is preferable as the metal reagent to be used, and the metal reagent is preferably used in combination with a reagent such as ammonium chloride and acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, tetrahydrofuran and the like, mixed solvents obtained by adding water thereto, and the like. The reaction temperature is preferably from room temperature to 100° C.

Step 2: The reaction reagent having a leaving group includes, for example, alkyl halides, alkyl triflate and the like. Organic bases such as triethylamine, N,N-diisopropylethylamine, and the like and inorganic bases such as potassium carbonate, cesium carbonate and the like are preferable as the base. 1,4-Dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from room temperature to 150° C.

Step 3: The borylation reagent to be used includes bis(pinacolato)diboron, and the tin reagent includes hexamethylditin and the like. The preferred palladium catalyst includes, for example, tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride and the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base used for borylation includes, for example, potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CO— in the compound of the present invention, as shown in the following reaction scheme, after reacting the anionic reagent prepared from Ar¹ ring with aldehyde (P-I) to obtain a corresponding alcohol (P-II), the synthesis can be performed by the same method as described above.

(Wherein, X^(P) is H or a halogen atom.)

Step 1: The reagent for preparing an anion in the reaction system includes, for example, n-butyllithium, isopropylmagnesium chloride-lithium chloride complex solution and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from −78° C. to 50° C., and particularly preferably from −40° C. to room temperature.

Step 2: Dess-Martin periodinane, 2-iodoxybenzoic acid, pyridinium chlorochromate or the like is preferable as the oxidizing agent to be used. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 3: The borylation reagent to be used includes, for example, bis(pinacolato)diboron, and the tin reagent includes, for example, hexamethylditin, and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the preferred palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes, for example, potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. The solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CO— in the compound of the present invention, after synthesizing the corresponding ketone (Q-II) using Ar¹ ring having the Weinreb amide (Q-II) as shown in the following reaction scheme, the synthesis can be performed by the same method as described above.

Step 1: The reagent for preparing an anion in the reaction system includes, for example, n-butyllithium, isopropylmagnesium chloride-lithium chloride complex solution, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from −78° C. to 50° C., and particularly preferably from −40° C. to room temperature.

Step 2: The borylation reagent to be used includes, for example, bis(pinacolato)diboron, and the tin reagent includes, for example, hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes, for example, potassium acetate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CH₂— in the compound of the present invention, synthesis can be performed by using the following synthesis methods.

For example, synthesis can be performed as shown in the following reaction scheme. That is, after bonding Ar¹ ring compound (R-II) having a reactive substituent such as a boronic acid derivative with benzyl bromide (R-I) by a cross-coupling reaction, by converting (R-III) to a boron compound, tin compound, or the like, then performing the cross-coupling reaction with the corresponding Ar² ring compounds, a biaryl bond can be formed to complete the synthesis. On the other hand, (R-III) can be directly used to perform cross-coupling reaction or the like with Ar² ring compounds having suitable reactive substituents without an operation of step 2.

Step 1: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 2: The borylation reagent to be used includes, for example, bis(pinacolato)diboron, and the tin reagent includes, for example, hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes, for example, potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly from preferably 70° C. to 120° C.

Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine or ethylenediamine is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CH₂— in the compound of the present invention, as shown in the following reaction scheme, after obtaining (S-II) by bonding to Ar¹ ring through an alkylation reaction using a nitrogen atom in the Ar¹ ring, the synthesis can be performed by the same method as described above.

Step 1: Triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate or the like is preferable as the base. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 120° C., and particularly preferably from 40° C. to 100° C.

Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 3: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CH₂— in the compound of the present invention, as shown in the following reaction scheme, a target compound in which amino group or alkoxy group is introduced can be synthesized using the aldehyde of intermediate (T-I) as a foothold.

(Wherein, R^(T1), R^(T2), R^(T3) are H atoms or C₁₋₆ alkyl groups.)

Step 1: A reductive amination reaction is performed using an amine suitable for the target compound. The imine reducing agent includes, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like. Preferred solvents include, for example, toluene, dichloromethane, dichloroethane, and the like. The reaction temperature is preferably from room temperature to 80° C.

Step 2: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like, is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like, is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

Step 3: The reducing agent to be used includes, for example, sodium borohydride, lithium borohydride, and the like. Preferred solvents include tetrahydrofuran, methanol, a mixed solvent thereof, and the like. The reaction temperature is preferably from 0° C. to room temperature.

Step 4: Alkyl halide, alkyl triflate or the like is used as a reagent having a leaving group. The base includes, for example, sodium hydride, potassium carbonate, cesium carbonate. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 80° C.

Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L¹ in the formula (I) is —CH₂— in the compound of the present invention, as shown in the following reaction scheme, a target compound having an amide group can be synthesized via functional group conversion of the ester group in intermediate (U-I).

(Wherein, R^(U) is a C₁₋₆ alkyl group.)

Step 1: The base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and the like, metal alkoxides such as sodium ethoxide, sodium methoxide, and the like, a solution thereof diluted with water, and the like. Here, the solvent is not particularly limited, and includes, for example, tetrahydrofuran, methanol, ethanol, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 0° C. to 60° C.

Step 2: The condensing agent to be used includes, for example, HATU, HOBt, HOAt, EDCI, and the like. The reaction is performed in the presence of no base or a base such as triethylamine, N,N-diisopropylethylamine, and the like. Tetrahydrofuran, dichloromethane, N,N-dimethylformamide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 100° C.

Step 3: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L in the formula (I) is —CH₂— in the compound of the present invention, the synthesis can also be performed by the method shown in the following reaction scheme. That is, after obtaining triazole (V-IV) by reacting the acetylene compound (V-III) with the (V-II) into which an azide group is introduced, the synthesis can be performed by the same method as described above.

Step 1: This reaction is a reaction of introducing an azido group using sodium azide. The solvent includes, for example, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 100° C.

Step 2: This reaction is a reaction of performing triazole ring synthesis using an alkyne compound corresponding to the target compound. Copper(I) iodide, copper(I) bromide or the like is preferable as the metal reagent, and if necessary, a ligand such as tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) is also added. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 80° C.

Step 3: Preferred palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, and the like, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. The solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CH₂— in the compound of the present invention, the synthesis can be performed also by the method shown in the following reaction scheme. That is, after obtaining (W-V) by a coupling reaction between boronic acid (W-I) and nitropyrazole ring (W-II), reducing a nitro group, and modifying an amino group, the target compound can be synthesized by the same method as described above.

(Wherein, R^(W1) and R^(W2) are substituents which form —NR^(W1)R^(W2) which may be included in R³ of the formula (I).)

Step 1: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 2: Iron, zinc, or the like is preferable as the metal reagent to be used, and is preferably used in combination with a reagent such as ammonium chloride, acetic acid, and the like. Preferred solvents include, for example, organic solvents such as ethanol, methanol and tetrahydrofuran, and mixed solvents obtained by adding water thereto, and the like. The reaction temperature is preferably from room temperature to 100° C.

Step 3: The reaction reagent having a leaving group includes, for example, alkyl halides, alkyl triflate, and the like. Organic bases such as triethylamine, N,N-diisopropylethylamine, or the like, or inorganic bases such as potassium carbonate, cesium carbonate, or the like is preferable as the base. 1,4-Dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from room temperature to 150° C.

Step 4: The borylation reagent includes, for example, bis(pinacolato)diboron, and the like. Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, XPhos-Pd-G2, or the like is preferable as the catalyst. If necessary, the ligand such as tricyclohexylphosphine, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Potassium acetate or the like is preferable as the base. Preferred solvents include, for example, 1,4-dioxane, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.

Step 5: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CHMe-, —C(═CH₂)—, or a 1,1-cyclopropropylidene group in the compound of the present invention, synthesis can be performed as shown in the following reaction scheme. That is, after reacting tosylhydrazone (X-III) with an Ar¹ ring compound having a halogen atom to obtain an exoolefin (X-IV), the target compound can be synthesized by reducing or cyclopropanating the olefin, and then deprotecting. The compound represented by formula (I) in which L¹ is —C(═CH₂)— can be synthesized by deprotecting (X-IV).

Step 1: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 2: This reaction is a reaction of forming tosylhydrazone using tosylhydrazine as a reagent. Preferred solvents include toluene, methanol, ethanol, and the like. The reaction temperature is preferably from room temperature to 120° C.

Step 3: This reaction is a reaction of synthesizing an exoolefin by performing a coupling reaction between tosylhydrazone and aryl halide. Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, or the like is preferable as the catalyst. If necessary, a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Preferred bases include cesium carbonate, lithium tert-butoxide, tripotassium phosphate. Preferred solvents include 1,4-dioxane, toluene, fluorobenzene, and the like. The reaction temperature is preferably from 50° C. to 150° C.

Step 4: This reaction is a reaction of reducing an olefin by combining a metal reagent such as palladium carbon (Pd/C) and a hydrogen source such as hydrogen gas. Ethanol, methanol, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 100° C.

Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

Step 6: This reaction is a reaction of converting an olefin to cyclopropane using trimethylsulfoxonium iodide. Preferred bases include, for example, sodium hydride, potassium tert-butoxide, and the like. Dimethyl sulfoxide, tetrahydrofuran or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 100° C.

Step 7: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate, or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L in the formula (I) is —CH(R¹¹)— in the compound of the present invention, synthesis can be performed by using the following methods.

For example, synthesis can be performed as shown in the following reaction scheme. That is, after reducing the ketone of (Y-I) prepared by the synthesis method described above, the target compound can be synthesized by deprotecting the amino group. It is also possible to modify the hydroxy group in intermediate (Y-II) by an alkylation reaction or the like.

(Wherein, R^(Y) is a substituent which forms —OR^(Y) which satisfies R¹¹ in the formula (I).)

Step 1: The reducing reagent includes, for example, sodium borohydride, lithium borohydride, and the like. Preferred solvents include, for example, tetrahydrofuran, methanol, ethanol, a mixed solvent thereof, and the like. The reaction temperature is preferably from 0° C. to 50° C.

Step 2: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 3: Alkyl halide, alkyl triflate or the like is used as the reagent having a leaving group. The base includes, for example, sodium hydride, potassium carbonate, cesium carbonate, and the like. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 80° C.

Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

When L¹ in the formula (I) is —CH(R¹¹)— in the compound of the present invention, the synthesis can be performed also as shown in the following reaction scheme. That is, after introducing an ethynyl group on the raw material aldehyde (Z-I), cyclization reaction is performed using (Z-IV) to obtain target isoxazole (Z-V) having R³ substituent. After modifying the hydroxy group of (Z-V) by an alkylation reaction or the like, the target compound can be synthesized by deprotecting the amino group.

(Wherein, R^(Z) is a substituent which forms —OR^(Z) which satisfies R¹¹ in the formula (I).)

Step 1: This reaction is an addition reaction of ethynylmagnesium bromide (Z-II) to aldehyde (Z-I). Tetrahydrofuran, dichloromethane, or the like is preferable as the solvent to be used. The reaction temperature is preferably from −78° C. to room temperature.

Step 2: This reaction is a reaction of constructing an isoxazole ring using an oxime reagent (Z-IV) corresponding to the target compound. Potassium carbonate, sodium carbonate, cesium carbonate, or the like is preferable as the base, and 1,4-dioxane, toluene, or the like is preferable as the solvent. The reaction temperature is preferably from 50° C. to 120° C.

Step 3: Alkyl halide, alkyl triflate or the like is used as the reagent having a leaving group. The base includes, for example, sodium hydride, potassium carbonate, cesium carbonate, and the like. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 80° C.

Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L¹ in the formula (I) is —S— or —SO— in the compound of the present invention, the synthesis can be performed using the following methods.

For example, synthesis can be performed as shown in the following reaction scheme. That is, after converting the intermediate (A′-I) obtained by the above-mentioned synthesis method into triflate (A′-II), a thiol side chain is introduced by a coupling reaction, and this compound (A′-III) is treated with a suitable base and subjected to an aromatic nucleophilic substitution reaction to be bonded with Ar¹ ring. If necessary, after this, the target compound can be synthesized by introducing the target side chain substituent using a halogen atom in Ar¹ as a foothold. If the Ar¹ compound used in step 3 has already been modified with R³, the operation in step 4 can be omitted.

Step 1: The triflation agent to be used include trifluoromethanesulfonic anhydride (Tf₂O), and the like and pyridine, triethylamine, N,N-diisopropylethylamine or the like is preferable as the base. Preferred solvents include, for example, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and the like. The reaction temperature is preferably from −20° C. to 50° C.

Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, or the like is preferable as the catalyst. If necessary, the ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Preferred bases include, for example, N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and the like. The solvent includes, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and the like. The reaction temperature is preferably from 50° C. to 150° C.

Step 3: Potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or the like is preferable as the base. Preferred solvents include, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 150° C.

Step 4: For introduction of the R³ substituent, a known method commonly used in the art can be adopted. For example, when the R³ substituent is introduced using boronic acid derivatives, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably form 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.

Further, for example, when an alcohol or an amine corresponding to the R³ substituent is reacted, preferred bases include, for example, organic bases such as triethylamine, N,N-diisopropylethylamine, and the like, and inorganic bases such as potassium carbonate, cesium carbonate, and the like. Here, the solvent is not particularly limited, and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 150° C.

Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably 0° C. to room temperature.

When L¹ in the formula (I) is —S— in the compound of the present invention, synthesis can be performed also as shown in the following reaction scheme. That is, since an aromatic nucleophilic substitution reaction can be used as a method for bonding with an Ar² ring such as pyrazole or the like, after the formation of a biaryl bond, the synthesis can be performed in the same manner as in the above scheme.

Step 1: Triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, or the like is preferable as the base to be used. Preferred solvents include, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 150° C.

Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, or the like is preferable as the catalyst. If necessary, the ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Preferred bases include N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and the like. The solvent includes, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and the like. The reaction temperature is preferably from 50° C. to 150° C.

Step 3: Potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or the like is preferable as the base. Preferred solvents include, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 150° C.

Step 4: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

When L¹ in the formula (I) is —SO— in the compound of the present invention, as shown in the following reaction scheme, the target compound can be synthesized by oxidizing sulfide (C′-I) to convert to sulfoxide (C′-II), and then performing deprotection.

Step 1: The oxidizing agent to be used includes, for example, 3-chloroperbenzoic acid and the like. The solvent includes, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.

Step 2: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate, or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.

Pharmaceutically acceptable salts of the compounds represented by formula (I) are not particularly limited as long as they are pharmaceutically acceptable salts, and include, for example, salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, and the like, salts with organic acids such as maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid, and the like, salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, aspartic acid, and the like, salts with alkali metals such as sodium, potassium, lithium, and the like, salts with alkaline earth metals such as calcium, magnesium, and the like, salts with metals such as aluminum, zinc, iron, and the like, salts with organic oniums such as tetramethylammonium, choline, and the like, and salts with organic bases such as ammonia, propanediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycyl alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenylamine, piperazine, tris(hydroxymethyl)aminomethane, and the like.

Further, the compounds represented by formula (I) or pharmaceutically acceptable salts thereof include various hydrates and solvates. The solvents of the solvates include, though not particularly limited, for example, methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butylmethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, benzene, toluene, N,N-dimethylformamide, dimethyl sulfoxide, and the like.

The medically acceptable salts of the compound represented by the formula (I) may be appropriately produced based on conventional knowledge in the art.

The compounds represented by formula (I) or pharmaceutically acceptable salts thereof include stereoisomers, racemates and all possible optically active substances thereof.

The compound represented by formula (I) of the present invention or the pharmaceutically acceptable salt thereof can be used in any formulation such as solid preparation, semi-solid preparation and liquid preparation, or any application such as oral and non-oral preparations (injections, percutaneous absorption agents, eye drops, suppositories, transnasal absorption agents, inhalants, and the like).

The pharmaceutical composition containing a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof is prepared using additives usually used for formulation. The additives for a solid preparation includes, for example, an excipient such as lactose, saccharose, glucose, corn starch, potatostarch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, calcium hydrogen phosphate, and the like, a binder such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, polyvinyl pyrrolidone, and the like, a disintegrating agent such as starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium and sodium carboxy methyl starch, and the like, a lubricant such as talc, stearic acids, and the like, a coating agent such as hydroxymethylpropylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose, and the like, and a coloring agent; the additives for a semisolid preparation include, for example, a substrate such as white petrolatum and the like; and the additives for a liquid preparation includes, for example, a solvent such as ethanol, and the like, a solubilizing agent such as ethanol, and the like, a preservative such as para-hydroxybenzoate, and the like, a isotonizing agent such as glucose, and the like, a buffer such as citric acid, and the like, an antioxidant such as L-ascorbic acid, and the like, a chelating agent such as EDTA, and the like, and a suspending agent and an emulsifying agent such as polysorbate 80 and the like.

The therapeutically effective amount of the active ingredient in the therapeutic agent or prophylactic agent in the present invention, which depends on the route of administration, the age and sex of the patient, and the severity of the disease, is usually of the order of 0.1 to 1000 mg/day, and the frequency of administration is usually one to three times/day to one to seven times/week. The preparation is preferably prepared so as to satisfy such conditions.

In the present invention, the term “prevention” means to prevent incidence or onset of diseases in an individual who is not affected by diseases or has not yet developed diseases and the term “treatment” means to cure, suppress, or remedy diseases or symptoms in an individual who has already been affected by diseases or has developed diseases.

EXAMPLES

Hereinafter, the present invention will be described in greater detail by way of working examples, but not limited thereto. Abbreviations in the present invention are as follows:

BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl DBU=1,8-diazabicyclo[5.4.0]-7-undecene

DMA=N,N-dimethylacetamide DMF=N,N-dimethylformamide

DMSO=dimethyl sulfoxide HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate NMP=1-methyl-2-pyrrolidone TFA=trifluoroacetic acid THF=tetrahydrofuran

The structure of the novel compound isolated was identified by ¹H-NMR and/or mass spectrometry using a single quadrupole instrumentation equipped with an electron spray source, or by other suitable analytical methods.

For the measurement of ¹H-NMR spectrum (400 MHz, DMSO-d₆, CDCl₃, or CD₃OD), the chemical shift (δ: ppm) and coupling constant (J: Hz) are shown. As for the result of mass spectrometry, the measured value observed as M⁺+H, that is, the value obtained by adding the mass of a proton (H⁺) to the molecular mass of a compound (M) is shown. The abbreviations used are as follows:

s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, brs=broad singlet, m=multiplet.

Reference Example 1 tert-Butyl (2-hydroxy-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)carbamate

tert-Butyl (2-(4-bromophenyl)-2-hydroxyethyl)carbamate (503 mg, 1.59 mmol) was dissolved in 1,4-dioxane (10 mL), then to the solution, bis(pinacolato)diboron (404 mg, 1.59 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (61 mg, 0.084 mmol) and potassium acetate (469 mg, 4.78 mmol) were added, and the mixture was stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (412 mg, 71%).

¹H-NMR (CDCl₃) δ: 7.81 (2H, d, J=7.8 Hz), 7.38 (2H, d, J=7.8 Hz), 4.90-4.86 (2H, m), 3.53-3.45 (1H, m)), 3.27-3.20 (1H, m), 1.45 (9H, s), 1.34 (12H, s).

Reference Example 2 tert-Butyl N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate

Step 1: 1-Bromo-4-(1,1-difluoro-3-nitropropan-2-yl)benzene

1-Bromo-4-[(E)-2-nitroethenyl]benzene (1 g) was dissolved in acetonitrile (4.4 mL), the solution was cooled to 0° C., then to the solution, (bromodifluoromethyl)trimethylsilane (1.03 mL), triphenylphosphine (1.38 g), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.06 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to −20° C., then to the mixture, chlorotrimethylsilane (0.11 mL) and methanol (0.89 mL) were added, and the mixture was stirred at the same temperature for 15 minutes and then heated to room temperature. Water (4 mL) and pyridine (0.42 mL) were added to the reaction mixture, and the mixture was stirred at 80° C. for 1.5 hours, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (785 mg).

¹H-NMR (CDCl₃) δ: 7.54 (2H, d, J=9.0 Hz), 7.18 (2H, d, J=8.2 Hz), 6.01 (1H, td, J=55.3, 2.7 Hz), 4.94 (1H, dd, J=13.7, 5.5 Hz), 4.83 (1H, ddd, J=71.4, 13.7, 7.3 Hz), 4.06-3.93 (OH, m).

Step, 2: tert-Butyl N-[2-(4-bromophenyl)-3,3-difluoropropyl]carbamate

1-Bromo-4-(1,1-difluoro-3-nitropropan-2-yl)benzene (785 mg) was suspended in a mixed solvent of ethanol (7 mL) and water (2 mL), then to the suspension, iron powder (470 mg) and ammonium chloride (450 mg) were added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, the mother liquor was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. This crude product was dissolved in dichloromethane (14 mL), then to the solution, di-tert-butyl dicarbonate (612 mg) and N,N-diisopropylethylamine (0.39 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (667 mg).

MS: m/z 294.1 (M-tBu+H)⁺.

Step 3: tert-Butyl N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate

tert-Butyl N-[2-(4-bromophenyl)-3,3-difluoropropyl]carbamate (667 mg) was dissolved in 1,4-dioxane (19 mL), then to the solution, bis (pinacolato)diboron (629 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (139 mg) and potassium acetate (561 mg) were added, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure to obtain a crude product of the title compound.

Reference Example 3 tert-Butyl N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate

Step 1: 1-(6-Chloropyridin-3-yl)-2-nitroethanol

Nitromethane (3 mL) and triethylamine (3 mL) were added to 6-chloropyridin-3-carbaldehyde (1 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

Step 2: tert-Butyl N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate

The crude product obtained in Step 1 was dissolved in THF (10 mL), then to the solution, zinc powder (2.31 g) and acetic acid (3 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. This crude product was dissolved in dichloromethane (14 mL), then to the solution, di-tert-butyl dicarbonate (1.54 g) and N,N-diisopropylethylamine (2 mL) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the title compound (651 mg).

MS: m/z 273.2 (M+H)⁺.

Reference Example 4 tert-Butyl N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate

Step 1: 1-(2-Chloropyrimidin-5-yl)-2-nitroethanol

Nitromethane (1 mL) and triethylamine (2 mL) were added to 2-chloropyrimidine-5-carbaldehyde (428 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

Step 2: tert-Butyl N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate

The crude product obtained in Step 1 was dissolved in THF (5 mL), then to the solution, zinc powder (981 mg) and acetic acid (0.86 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. This crude product was dissolved in dichloromethane (5 mL), then to the solution, di-tert-butyl dicarbonate (1.31 g) and N,N-diisopropylethylamine (1.6 mL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (208 mg).

MS: m/z 274.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 8.64 (2H, s), 4.96-4.94 (2H, m), 3.55-3.51 (1H, m), 3.34-3.27 (1H, m), 1.45 (9H, s).

Reference Example 5 tert-Butyl N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl]carbamate

Step 1: 1-(5-Chloropyrazin-2-yl)-2-nitroethanol

Nitromethane (1 mL) and triethylamine (1 mL) were added to 5-chloropyrazine-2-carbaldehyde (826 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

Step 2: tert-Butyl N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl]carbamate

The crude product obtained in Step 1 was dissolved in THF (5 mL), the solution was cooled to 0° C., then to the solution, di-tert-butyl dicarbonate (1.06 g), zinc powder (792 mg) and acetic acid (0.7 mL) were added, and then the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (57.5 mg).

MS: m/z 218.1 (M-tBu+H)⁻.

Reference Example 6 tert-Butyl 3-(6-chloropyridin-3-yl)-3-fluoroazetidine-1-carboxylate

Step 1: tert-Butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazetidine-1-carboxylate

5-Bromo-2-chloropyridine (385 mg) was dissolved in THF (10 mL), the solution was cooled to −78° C., and to the solution, n-butyllithium (1.2 mL) was added dropwise. After stirring at the same temperature for 1 hour, then to the solution, a solution (2 mL) of 1-(tert-butoxycarbonyl)-3-azetidinone (342 mg) in THF was added, and the temperature of the solution was raised to room temperature over 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (209 mg).

MS: m/z 285.0 (M+H)⁺.

Step 2: tert-Butyl 3-(6-chloropyridin-3-yl)-3-fluoroazetidine-1-carboxylate

tert-Butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazetidine-1-carboxylate (100 mg) was dissolved in dichloromethane (1.8 mL), the solution was cool to −78° C., then to the solution bis(2-methoxyethyl)aminosulfur trifluoride (0.078 mL) was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was heated to room temperature, then to the solution, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solution was concentrated under reduced pressure to obtain a crude product of the title compound (40 mg).

MS: m/z 287.0 (M+H)⁺.

Reference Example 7 N-[3-[(6-Chloropyridin-3-yl)methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide

2-Chloro-5-iodopyridine (479 mg) was dissolved in THF (10 mL) and to the solution, isopropylmagnesium bromide (1 M solution in THF, 2.0 mL) was added dropwise at 0° C. After stirring the solution at the same temperature for 1 hour, then to the solution, copper(I) iodide (38.1 mg) was added, and the mixture was cooled to −30° C. A solution (2 mL) of 1-tert-butylsulfinyl-5-oxa-1-azaspiro[2.3]hexane (189 mg) in THF was added dropwise to the reaction mixture, the mixture was heated to room temperature, and the mixture was stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (108 mg).

MS: m/z 303.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 8.33 (1H, s), 7.71 (1H, d, J=7.3 Hz), 7.30 (1H, d, J=8.2 Hz), 4.83 (1H, d, J=6.4 Hz), 4.66-4.56 (3H, m), 3.59 (1H, s), 3.41 (2H, q, J=14.5 Hz), 1.22 (9H, s).

Reference Example 8 tert-Butyl N-[(2R)-2-(6-chloropyridin-3-yl)-2-fluoroethyl]carbamate

tert-Butyl N-[(2S)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate (164 mg) obtained by chiral separation of the racemic compound of Reference Example 3 was added to dichloromethane (3 mL), and to the mixture, bis(2-methoxyethyl)aminosulfur trifluoride (0.13 mL) was added dropwise at 0° C. After stirring the mixture at the same temperature for 1 hour, the reaction mixture was directly purified by silica gel column chromatography to obtain the title compound (37.5 mg).

MS: m/z 275.1 (M+H)⁺.

Reference Example 9 tert-Butyl N-[(2R)-2-(2-chloropyrimidin-5-yl)-2-fluoroethyl]carbamate

tert-Butyl N-[(2S)-2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate (547 mg) obtained by chiral separation of the racemic compound of Example 4 was dissolved in dichloromethane (10 mL), and to the solution, bis(2-methoxyethyl)aminosulfur trifluoride (0.44 mL) was added dropwise at 0° C. After stirring the mixture at the same temperature for 1 hour, the reaction mixture was directly purified by silica gel column chromatography to obtain the title compound (83.3 mg).

MS: m/z 276.2 (M+H)⁺.

Reference Example 10 2-[2-(6-Chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione

Step 1: Ethyl 2-(6-chloropyridin-3-yl)-2,2-difluoroacetate

2-Chloro-5-iodopyridine (2 g) was dissolved in DMSO (33 mL), then to the solution, ethyl bromodifluoroacetate (1.87 g) and copper powder (1.33 g) were added, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, an aqueous disodium hydrogen phosphate solution was added to the solution, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (958 mg).

MS: m/z 236.1 (M+H)⁺.

Step 2: 2-(6-Chloropyridin-3-yl)-2,2-difluoroethanol

Ethyl 2-(6-chloropyridin-3-yl)-2,2-difluoroacetate (958 mg) was dissolved in methanol (20 mL), the solution was cooled to 0° C., and to the solution, sodium borohydride (308 mg) was added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (493 mg).

MS: m/z 194.1 (M+H)⁺.

Step 3: 2-[2-(6-Chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione

2-(6-Chloropyridin-3-yl)-2,2-difluoroethanol (493 mg), phthalimide (487 mg) and triphenylphosphine (1 g) were suspended in THF (5 mL), then to the suspension, diisopropyl azodicarboxylate (0.74 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (395 mg).

MS: m/z 323.1 (M+H)⁺.

Example 1 4-[4-(2-Aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]benzonitrile (Compound No. 4)

Step 1: 3-Amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile

3-Amino-4-chlorobenzonitrile (700 mg, 4.59 mmol) was dissolved in 1,4-dioxane (23 mL), then to the solution, bis(pinacolato)diboron (1.28 g, 5.05 mmol), tris(dibenzylideneacetone)dipalladium (126 mg, 0.14 mmol), tricyclohexylphosphonium tetrafluoroborate (101 mg, 0.28 mmol) and potassium acetate (1.35 g, 13.8 mmol) were added, and the mixture was stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and filtered through Celite, then the mother liquor was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (541 mg, 48%).

¹H-NMR (CDCl₃) δ: 7.65 (1H, d, J=7.3 Hz), 6.89 (1H, d, J=7.8 Hz), 6.81 (1H, s), 4.93 (2H, brs), 1.35 (12H, s).

Step 2: tert-Butyl (2-(2′-amino-4′-cyano-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate

To a solution of 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (245 mg, 1.00 mmol) in toluene/water (=4/1, 5 mL), tert-butyl N-[2-(4-bromophenyl)-2-oxo-ethyl]carbamate (315 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium (57.9 mg, 0.050 mmol) and potassium carbonate (416 mg, 3.00 mmol) were added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. Water was added to the mother liquor, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (280 mg, 80%).

MS: m/z 296.1 (M-tBu+H)⁺.

Step 3: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate

tert-Butyl (2-(2′-amino-4′-cyano-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate (50.8 mg, 0.145 mmol) was dissolved in toluene (2 mL), then to the solution, 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (30.9 mg, 0.145 mmol), tris(dibenzylideneacetone)dipalladium (6.6 mg, 0.072 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.4 mg, 0.015 mmol) and sodium tert-butoxide (27.8 mg, 0.289 mmol) were added, and the mixture was stirred at 150° C. under microwave irradiation for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 4: 4-[4-(2-Aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]benzonitrile

Dichloromethane (2 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (2.09 mg).

Exact MS: 428.2

Obs. MS (M+H)+: 429.4

Example 2 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile (Compound No. 6)

Step 1: 4-Chloro-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile

1,4-Dioxane (6.7 mL) was added to 3-bromo-4-chlorobenzonitrile (578 mg, 2.67 mmol) and N,2-dimethyl-5-phenylpyrazole-3-amine (500 mg, 2.67 mmol), and to the mixture, tris(dibenzylideneacetone)dipalladium (122 mg, 0.134 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (232 mg, 0.401 mmol), and cesium carbonate (2.18 g, 6.68 mmol) were added, and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (512 mg, 59%).

MS: m/z 323.1 (M+H)⁺.

Step 2: 3-[Methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-Chloro-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile (256 mg, 0.792 mmol) was dissolved in 1,4-dioxane (2.6 mL), then to the solution, bis(pinacolato)diboron (302 mg, 1.19 mmol), bis(tricyclohexylphosphine)palladium dichloride (58.5 mg, 0.0792 mmol), and potassium acetate (233 mg, 2.38 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and filtered through Celite, and then the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.

MS: m/z 415.0 (M+H)⁺.

Step 3: tert-Butyl N-[2-[2-[4-cyano-2-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]phenyl]pyrimidin-5-yl]ethyl]carbamate

The crude product obtained in Step 2 was dissolved in 1,4-dioxane (2.6 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (50.0 mg, 0.194 mmol), tetrakis(triphenylphosphine)palladium (22.4 mg, 0.0194 mmol), potassium carbonate (80.4 mg, 0.582 mmol) and water (0.1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, ethyl acetate and water were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 510.0 (M+H)⁺.

Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (48.3 mg).

Exact MS: 409.2

Obs. MS (M+H)⁺: 410.4

Example 3 4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 7)

Step 1: 4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile

4-Bromo-3-hydroxybenzonitrile (1.19 g, 6.0 mmol) was dissolved in DMF (10 mL), then to the solution, 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (1.28 g, 6.0 mmol) and potassium carbonate (2.49 g, 18 mmol) were added to the mixture, and the mixture was stirred at 150° C. for 23 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (1.23 g, 54%).

Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yloxy)-[1,1′-biphenyl]-4-ylethyl)carbamate

4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile (110 mg, 0.29 mmol) was dissolved in toluene/water (=4/1) mixed solution (2.5 mL), then to the solution, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (132 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (16.9 mg, 0.015 mmol) and potassium carbonate (121 mg, 0.88 mmol) were added, and the mixture was stirred at 110° C. for 10 hours. The reaction mixture was cooled to room temperature, water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (140 mg, 93%).

MS: m/z 516.3 (M+H)⁺.

Step 3: 4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate (140 mg, 0.27 mmol) was dissolved in 1,4-dioxane (2 mL), then to the solution, a 4 M (=mol/L) hydrochloric acid/1,4-dioxane solution (2 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the crude product was dissolved in a mixed solution of ethyl acetate (50 mL) and 2 M hydrochloric acid (20 mL), and the target compound was back-extracted into an aqueous layer. Then, methanol/dichloromethane (=1/4) mixed solution (50 mL) and a 2 M aqueous sodium hydroxide solution (22 mL) were added to the mixture and the target compound was extracted into an organic phase. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (84.1 mg).

Exact MS: 415.2

Obs. MS (M+H)⁺: 416.2

Example 4 4-[4-(2-Amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 11)

Step 1: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-methoxyethyl)carbamate

tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-hydroxyethyl)carbamate (29 mg, 0.055 mmol) synthesized by the same method as in Example 3 was dissolved in DMF (1 mL), then to the solution, sodium hydride (2.7 mg) was added, and the mixture was stirred at room temperature for 5 minutes. Iodomethane (4.2 μL, 0.066 mmol) was added to this reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 2: 4-[4-(2-Amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

The crude product obtained in Step 1 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (8.7 mg).

Exact MS: 445.2

Obs. MS (M+H)⁺: 446.2

Example 5 4-[4-(2-Amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 13)

Step 1: 2-((tert-Butoxycarbonyl)amino)-1-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethylmethanesulfonate

tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-hydroxyethyl)carbamate (60.9 g, 0.115 mmol) synthesized by the same method as in Example 3 was dissolved in THF (2 mL), then to the solution, triethylamine (48 μL, 0.34 mmol) and methanesulfonyl chloride (11 μL, 0.14 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 610.3 (M+H)⁺.

Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-phenoxyethyl)carbamate

The crude product obtained in Step 1 was dissolved in DMF (2 mL), then to the solution, phenol (10.8 mg, 0.115 mmol) and potassium carbonate (47.5 mg, 0.34 mmol) were added, and the mixture was stirred at 100° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 608.3 (M+H)⁺.

Step 3: 4-[4-(2-Amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

The crude product obtained in Step 2 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.5 mg).

Exact MS: 507.2

Obs. MS (M+H)⁺: 508.2

Example 6 4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 17)

Step 1: tert-Butyl (2-(4′-cyano-2′-hydroxy-[1,1′-biphenyl]-4-yl)ethyl)carbamate

To a solution (50 mL) of 4-bromo-3-hydroxybenzonitrile (8.6 g, 43.4 mmol) in toluene/water (=9/1), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (22.7 g, 65.1 mmol), tetrakistriphenylphosphine palladium (5.0 g, 4.34 mmol), and potassium carbonate (11.9 g, 86.1 mmol) were added, and the mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, the mother liquor was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (5.0 g, 35%).

Step 2: tert-Butyl (2-(2′-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate

To a solution of tert-butyl (2-(4′-cyano-2′-hydroxy-[1,1′-biphenyl]-4-yl)ethyl)carbamate (2.8 g, 8.3 mmol) in DMF (15 mL), 4,6-dichloro-2-methylpyrimidine (1.35 g, 8.28 mmol) and cesium carbonate (5.38 g, 16.6 mmol) were added, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.8 g, 46%).

MS: m/z 464.8 (M+H)⁺.

Step 3: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-(piperidin-1-ylpyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate

tert-Butyl (2-(2′-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate (100 mg, 0.216 mmol) was dissolved in DMF (3 mL), then to the solution, piperidine (0.043 mL, 0.432 mmol) and cesium carbonate (140 mg, 0.431 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, the mixture was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 514.3 (M+H)⁺.

Step 4: 4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile

TFA (0.5 mL) was added to a solution of the crude product obtained in Step 3 in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (57.2 mg).

Exact MS: 413.2

Obs. MS (M+H)⁺: 414.0

¹H-NMR (DMSO-d₆) δ: 7.73 (1H, d, J=8.4 Hz), 7.68 (1H, s), 7.61 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=7.6 Hz), 7.21 (2H, d, J=7.6 Hz), 6.03 (1H, s), 3.52 (4H, bs), 2.75-2.78 (2H, m), 2.64 (2H, s), 2.15 (3H, s), 1.59 (2H, s), 1.45 (4H, bs).

Example 7 4-[4-(2-Aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 21)

Step 1: tert-Butyl (2-(4′-cyano-2′-((6-(2-cyanophenyl)-2-methylpyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate

An intermediate of tert-butyl (2-(2′-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate (100 mg, 0.215 mmol) obtained in Example 6 was dissolved in 1,4-dioxane (2 mL), then to the solution, potassium carbonate (59 mg, 0.43 mmol), 2-cyanophenylboronic acid (47 mg, 0.32 mmol), and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) were added, and the mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 2: 4-[4-(2-Aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile

The crude product obtained in Step 1 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.4 mg).

Exact MS: 431.2

Obs. MS (M+H)⁺: 431.9

¹H-NMR (DMSO-d₆) δ: 8.01-7.99 (2H, m), 7.95-7.93 (1H, m), 7.89-7.82 (2H, m), 7.74-7.70 (2H, m), 7.44-7.39 (3H, m), 7.28-7.23 (2H, m), 3.23 (2H, s), 1.90 (3H, s), 1.23 (2H, s).

Example 8 4-[4-(2-Aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 47)

Step 1: 4-Chloro-2-methyl-6-(neopentyloxy)pyrimidine

To a stirred mixture of sodium hydride (82 mg, 3.4 mmol) suspended in THF (4 mL), a solution of 2,2-dimethylpropan-1-ol (323 mg, 3.68 mmol) in THF (0.5 mL) was added dropwise at room temperature and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was cooled to 0° C., a solution of 4,6-dichloro-2-methylpyrimidine (400 mg, 2.45 mmol) in THF (0.5 mL) was added dropwise to the mixture, and the mixture was stirred at 0° C. for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (245 mg, 47%).

Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-(neopentyloxy)pyrimidin-4-yloxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate

tert-Butyl (2-(4′-cyano-2′-hydroxy-[1,1′-biphenyl]-4-yl)ethyl)carbamate (50 mg, 0.148 mmol) was dissolved in DMF (1 mL), then to the solution, 4-chloro-2-methyl-6-(neopentyloxy)pyrimidine (63.5 mg, 0.296 mmol) and cesium carbonate (96.4 mg, 0.296 mmol) were added, and the mixture was stirred at 70° C. overnight. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 517.0 (M+H)⁺.

Step 3: 4-[4-(2-Aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxybenzonitrile

Dichloromethane (2 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (21.4 mg).

Exact MS: 416.2

Obs. MS (M+H)+: 417.3

Example 9 4-[4-[2-(3-Hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 58)

Step 1: 4-[4-[2-(3-Hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (54 mg, 0.13 mmol) obtained in Example 3 was dissolved in DMF (1 mL), then to the solution, 3-bromopropan-1-ol (0.014 ml, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) were added, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by HPLC to obtain the target compound (11.3 mg).

Exact MS: 473.2

Obs. MS (M+H)⁺: 474.5

Example 10 4-[4-(2-Amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 59)

Step 1: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-(2-tosylhydrazono)ethyl)carbamate

tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate (855.8 mg, 1.62 mmol) synthesized by the same method in Example 3 was dissolved in toluene (8 mL), then to the solution, p-toluenesulfonyl hydrazide (301 mg, 1.62 mmol) was added, and the mixture was stirred at 110° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

MS: m/z 698.2 (M+H)⁺.

Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-phenylethyl)carbamate

An aliquot (30 mg) of the crude product obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), then to the solution, phenylboronic acid (11 mg, 0.086 mmol) and potassium carbonate (24 mg, 0.17 mmol) were added, and the mixture was stirred at 110° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 592.3 (M+H)⁺.

Step 3: 4-[4-(2-Amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

The crude product obtained in Step 2 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (3.1 mg).

Exact MS: 491.2

Obs. MS (M+H)⁺: 492.5

Example 11 4-(2-Amino-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 131)

Step 1: 3-(2-Methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroinden-5-yl)benzonitrile

4-Bromo-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (300 mg, 0.800 mmol) was dissolved in 1,4-dioxane (2 mL), then to the solution, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroinden-1-one (289 mg, 1.12 mmol), tetrakis(triphenylphosphine)palladium (46.2 mg, 0.0400 mmol), potassium carbonate (332 mg, 2.40 mmol) and water (0.5 mL) were added, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (290 mg, 85%).

MS: m/z 427.2 (M+H)⁺.

Step 2: 4-(2-Bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

3-(2-Methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroinden-5-yl)benzonitrile (290 mg, 0.680 mmol) was dissolved in a mixed solvent (6 mL) of chloroform/ethyl acetate (=1/1), then to the solution, copper(II) bromide (304 mg, 1.36 mmol) was added, and the mixture was stirred at 90° C. for 7 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (26.0 mg, 8%).

MS: m/z 505.1 (M+H)⁺.

Step 3: 4-[2-[(2,4-Dimethoxyphenyl)methylamino]-1-oxo-2,3-dihydroinden-5-yl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

4-(2-Bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (26.0 mg, 0.0514 mmol) was dissolved in DMF (I mL), then to the solution, 2,4-dimethoxybenzenemethanamine (12.9 mg, 0.0772 mmol) and triethylamine (0.022 mL, 0.154 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 4: 4-(2-Amino-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

TFA (1 mL) was added to the crude product obtained in Step 3, and the mixture was stirred at 120° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (6.00 mg).

Exact MS: 441.2

Obs. MS (M+H)⁺: 442.2

Example 12 4-[4-(2-Amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 149)

Step 1: 4-(3-fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

4-Bromo-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (188 mg, 0.500 mmol) was dissolved in 1,4-dioxane (4 mL), then to the solution, 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (250 mg, 1.00 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (36.6 mg, 0.0500 mmol), potassium carbonate (415 mg, 3.00 mmol) and water (1 mL) were added, and the mixture was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (174 mg, 83%).

MS: m/z 419.2 (M+H)⁺.

Step 2: 4-[3-Fluoro-4-(1-hydroxy-2-nitroethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

4-(3-Fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (174 mg, 0.416 mmol) was dissolved in THF (4 mL), then to the solution, nitromethane (0.5 mL) and triethylamine (1 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

MS: m/z 480.2 (M+H)⁺.

Step 3: 4-[4-(2-Amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile

Zinc powder (500 mg, 7.64 mmol) and acetic acid (4 mL) were added to the crude product obtained in Step 2, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite and concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.7 mg).

Exact MS: 449.2

Obs. MS (M+H)⁺: 450.2

Example 13 4-[4-[(1R)-2-Amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile (Compound No. 170)

Step 1: Ethyl 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate

DMSO (120 mL) was added to 4-fluoro-3-methoxybenzonitrile (15.1 g, 100 mmol), ethyl 1H-pyrazole-4-carboxylate (15.4 g, 110 mmol), and potassium carbonate (27.6 g, 200 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was stirred. The precipitated solid was collected by filtration through a glass filter and dried to obtain the target compound (22.8 g, 84%).

MS: m/z 272.0 (M+H)⁺.

Step 2: 1-(4-Cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid

Ethyl 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate (11.0 g, 40.5 mmol) was dissolved in a mixed solvent of THF (40 mL)/methanol (40 mL), then to the solution, a 2 M aqueous sodium hydroxide solution (40.5 mL, 81.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After adding 2M hydrochloric acid to the reaction mixture and stirring the mixture, water was further added to the solution to precipitate the target compound. The target compound was collected by filtration with a glass filter and dried to obtain the target compound (7.38 g, 75%).

MS: m/z 244.0 (M+H)⁺.

Step 3: 3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile

To 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid (7.38 g, 30.3 mmol), DMF (40 mL) and 1,1′-carbonyldime (5.90 g, 36.4 mmol) were added and the mixture was stirred for 2 hours (reaction mixture A). Nitromethane (2.78 g, 45.5 mmol) and DMF (40 mL) were added to another reaction vessel, sodium hydride (1.59 g, 36.4 mmol) was further added, and the mixture was stirred for 2 hours to separately prepare another solution (reaction mixture B). The reaction mixture B was cooled to 0° C., the reaction mixture A was added dropwise to the reaction mixture B, and then the mixture was heated to 100° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the target compound was precipitated. The precipitate was collected by filtration with a glass filter and dried to obtain the target compound (8.70 g, quant.).

MS: m/z 287.0 (M+H)⁺.

Step 4: 3-Hydroxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile

3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile (4.50 g, 15.7 mmol) was dissolved in DMF (40 mL), then to the solution, lithium chloride (6.67 g, 157 mmol) was added, and the mixture was stirred at 150° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 273.0 (M+H)⁺.

Step 5: 3-(2-Methyl-6-phenylpyrimidin-4-yl)oxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile

The crude product obtained in Step 4 was dissolved in DMF (40 mL), then to the solution, 4-chloro-2-methyl-6-phenylpyrimidine (3.54 g, 17.3 mmol) and potassium carbonate (4.35 g, 31.4 mmol) were added, and the mixture was stirred at 100° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure to obtain the target compound (2.69 g, 39%).

MS: m/z 441.1 (M+H)⁺.

Step 6: tert-Butyl N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-oxoethyl]carbamate

THF (40 mL) and acetic acid (1.83 g, 30.5 mmol) were added to 3-(2-methyl-6-phenylpyrimidin-4-yl)oxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile (2.69 g, 6.11 mmol), di-tert-butyl dicarbonate (4.00 g, 18.3 mmol) and zinc powder (2.00 g, 30.5 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (540 mg, 17%).

MS: m/z 511.2 (M+H)⁺.

Step 7: tert-Butyl N-[(2R)-2-[I-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-hydroxyethyl]carbamate

tert-Butyl N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-oxoethyl]carbamate (106 mg, 0.208 mmol) and (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (5.8 mg, 0.021 mmol) were dissolved in dichloromethane (1 mL) and the solution was cooled to 0° C. Dimethyl sulfide borane (47.3 mg, 0.633 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for 10 hours. Methanol and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 513.2 (M+H)⁺.

Step 8: 4-[4-[(1R)-2-Amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile

The crude product obtained in Step 7 was dissolved in dichloromethane (1 mL), TFA (1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (18.6 mg).

Exact MS: 412.2

Obs. MS (M+H)⁺: 413.2

Example 14 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 208)

Step 1: 3-(6-Chloro-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile

4-Fluoro-3-hydroxybenzonitrile (3.7 g, 27 mmol) was dissolved in DMF (90 mL), then to the solution, 4,6-dichloro-2-methylpyrimidine (6.6 g, 40 mmol) and potassium carbonate (7.5 g, 54 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (6.5 g).

MS: m/z 264.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 7.61 (1H, dq, J=8.7, 2.1 Hz), 7.56 (1H, dd, J=7.1, 2.2 Hz), 7.32 (1H, dd, J=9.5, 8.5 Hz), 6.90 (1H, s), 2.51 (3H, s).

Step 2: 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile

THF (12.6 mL) was added to 3-(6-chloro-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile (1.0 g, 3.79 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (557 mg, 0.759 mmol), then to the mixture, cyclopentyl zinc bromide (1.22 g, 5.69 mmol) was added dropwise, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (888 mg).

MS: m/z 298.1 (M+H)⁺.

Step 3: 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile

3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile (100 mg, 0.336 mmol) was dissolved in DMSO (0.5 mL), then to the solution, 4-iodo-1H-pyrazole (65.2 mg, 0.336 mmol) and potassium carbonate (93.0 mg, 0.673 mmol) were added, and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (78.9 mg).

MS: m/z 472.1 (M+H)⁺.

Step 4: 3-(6-Cyclopentyl-2-methylpyrimidin-1-yloxy-4-(4-iodopyrazol-1-yl)benzonitrile

3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile (34.2 mg, 0.0726 mmol) was added to 1,4-dioxane (0.4 mL), then to the solution, tert-butyl 3-oxopiperazine-1-carboxylate (16 mg, 0.080 mmol), copper(I) iodide (2.8 mg, 0.015 mmol), trans-1,2-cyclohexanediamine (1.7 mg, 0.015 mmol) and tripotassium phosphate (46.2 mg, 0.218 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 5: 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]benzonitrile

Dichloromethane (1 mL) and TFA (1 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (7.3 mg).

Exact MS: 443.2

Obs. MS (M+H)⁺: 444.3

Example 15 3-(2-Methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazepan-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 219)

Step 1: 3-Fluoro-4-(4-iodopyrazol-1-yl)benzonitrile

DMF (8.6 mL) was added to 3,4-difluorobenzonitrile (430 mg, 3.09 mmol), 4-iodo-1H-pyrazole (500 mg, 2.58 mmol), and cesium carbonate (1.68 g, 5.16 mmol), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (428 mg, 53%).

¹H-NMR (CDCl₃) δ: 8.18 (1H, d, J=2.7 Hz), 8.15 (1H, t, J=8.2 Hz), 7.79 (1H, s), 7.60-7.55 (2H, m).

Step 2: 4-(4-Iodopyrazol-1-yl)-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile

NMP (2.6 mL) was added to 3-fluoro-4-(4-iodopyrazol-1-yl)benzonitrile (201 mg, 0.642 mmol), 2-methyl-5-phenyl-4H-pyrazol-3-one (123 mg, 0.706 mmol), and potassium carbonate (177 mg, 1.28 mmol), and the mixture was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (198 mg, 66%).

MS: m/z 468.1 (M+H)⁺.

Step 3: tert-Butyl 4-[1-[4-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxyphenyl]pyrazol-4-yl]-5-oxo-1,4-diazepane-1-carboxylate

tert-Butyl 5-oxo-1,4-diazepane-1-carboxylate (24 mg, 0.11 mmol), copper(I) iodide (3.7 mg, 0.020 mmol), trans-1,2-cyclohexanediamine (2.2 mg, 0.020 mmol) and tripotassium phosphate (62.7 mg, 0.295 mmol) were added to a solution (0.5 mL) of 4-(4-Iodopyrazol-1-yl)-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (46 mg, 0.098 mmol) in 1,4-dioxane, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 4: 3-(2-Methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazepan-1-yl)pyrazol-1-yl]benzonitrile

The crude product obtained in Step 3 was dissolved in dichloromethane (1 mL), TFA (1 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.7 mg).

Exact MS: 453.2

Obs. MS (M+H)⁺: 454.3

Example 16 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (Compound No. 250)

Step 1: 4-Bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile

NMP (400 mL) was added to 4-bromo-3-fluorobenzonitrile (40.0 g, 200 mmol), 6-methylpyridine-2,4-diol (30.0 g, 240 mmol), and sodium carbonate (53.0 g, 500 mmol), and the mixture was stirred at 160° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethyl acetate was added to the concentrated crude product to prepare a suspension, heptane was further added to the suspension, and the precipitated solid was collected by filtration through a glass filter. The solid was vacuum dried to obtain the target compound (20.3 g, 33%).

MS: m/z 305.0 (M+H)⁺.

¹H-NMR (DMSO-d₆) δ: 11.47 (1H, s), 8.00 (1H, d, J=8.2 Hz), 7.92 (1H, d, J=1.8 Hz), 7.73 (1H, dd, J=8.2, 2.3 Hz), 5.89 (1H, d, J=1.8 Hz), 5.15 (l H, d, J=2.7 Hz), 2.15 (3H, s).

Step 2: [4-(2-Bromo-5-cyanophenoxy)-6-methylpyridin-2-yl]trifluoromethanesulfonate

Dichloromethane (22 mL) was added to 4-bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile (2.7 g, 8.85 mmol), the mixture was cooled to 0° C., and then trifluoromethanesulfonic anhydride (3.25 g, 11.5 mmol) was added to the mixture. Pyridine (2.1 mL, 26.5 mmol) was added dropwise to this reaction mixture at the same temperature, then the temperature was raised to room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 436.9 (M+H)⁺.

Step 3: 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile

The crude product obtained in Step 2 was dissolved in DMSO (18 mL), then to the solution, morpholine (1.16 g, 13.3 mmol) and N, N-diisopropylethylamine (4.73 mL, 26.5 mmol) were added, and the mixture was stirred at 70° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethanol was added to the concentrated crude product and dried overnight. The precipitated target compound was collected by filtration through a glass filter and dried to obtain the target compound (1.87 g, 57%).

MS: m/z 374.0 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 7.77 (I H, d, J=8.2 Hz), 7.35 (1H, dd, J=8.2, 1.8 Hz), 7.29 (1H, d, J=1.8 Hz), 6.02 (1H, d, J=1.4 Hz), 6.00 (1H, d, J=1.4 Hz), 3.80 (4H, t, J=5.0 Hz), 3.48 (4H, t, J=4.8 Hz), 2.36 (3H, s).

Step 4: 3-(2-methyl-6-morpholin-4-ylpyridin-4-yloxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-Bromo-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (790 mg, 2.11 mmol) was dissolved in 1,4-dioxane (11 mL), then to the solution, bis(pinacolato)diboron (804 mg, 3.17 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (76.4 mg, 0.106 mmol), and potassium acetate (415 mg, 4.22 mmol) were added, and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (567 mg).

MS: m/z 422.3 (M+H)⁺.

Step 5: tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate

3-(2-Methyl-6-morpholin-4-ylpyridin-4-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (222 mg, 0.527 mmol) was dissolved in 1,4-dioxane (1.8 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (90.5 mg, 0.351 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (12.8 mg, 0.0176 mmol), potassium carbonate (97.1 mg, 0.702 mmol), and water (0.4 mL) were added, and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (71.9 mg, 40%).

MS: m/z 517.3 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 8.61 (2H, s), 8.05 (1H, d, J=8.2 Hz), 7.61 (11H, dd, J=8.2, 1.4 Hz), 7.44 (1H, d, J=1.4 Hz), 6.01 (1H, d, J=1.4 Hz), 5.94 (1H, d, J=1.8 Hz), 4.70 (1H, brs), 3.78 (4H, t, J=4.8 Hz), 3.41 (4H, t, J=4.8 Hz), 3.36 (2H, q, J=6.6 Hz), 2.82 (2H, t, J=6.6 Hz), 2.29 (3H, s), 1.43 (9H, s).

Step 6: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile

tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (71.9 mg, 0.139 mmol) was dissolved in dichloromethane (1 mL), then TFA (1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (63.62 mg).

Exact MS: 416.2

Obs. MS (M+H)⁺: 417.4

¹H-NMR (CD₃OD) δ: 8.79 (2H, s), 8.33 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.0, 1.6 Hz), 7.79 (l H, d, J=1.4 Hz), 6.46 (1H, d, J=1.8 Hz), 6.39 (1H, d, J=1.8 Hz), 3.79 (4H, t, J=5.0 Hz), 3.55 (4H, t, J=5.0 Hz), 3.25 (2H, t, J=7.8 Hz), 3.04 (2H, t, J=7.8 Hz), 2.50 (3H, s).

Example 17 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 261)

Step 1: 4-Bromo-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile

4-Bromo-3-fluorobenzonitrile (2.14 g, 10.7 mmol) and 2-methyl-5-propan-2-ylpyrazole-3-ol (1.50 g, 10.7 mmol) were dissolved in DMA (21 mL), then potassium carbonate (4.44 g, 32.1 mmol) was added to the solution, and the mixture was stirred at 130° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.06 g, 31%).

MS: m/z 322.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 7.77 (1H, d, J=8.2 Hz), 7.34-7.32 (2H, m), 5.52 (1H, s), 3.70 (3H, s), 2.94-2.87 (1H, m), 1.25 (6H, d, J=6.9 Hz).

Step 2: 3-(2-Methyl-5-propan-2-ylpyrazol-3-yloxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-Bromo-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (646 mg, 2.02 mmol) was dissolved in 1,4-dioxane (10 mL), then to the solution, bis(pinacolato)diboron (615 mg, 2.42 mmol), bis(triphenylphosphine)palladium dichloride (70.8 mg, 0.101 mmol) and potassium acetate (396 mg, 4.03 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 368.2 (M+H)⁺.

Step 3: tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate

To a solution (13.5 mL) of the crude product in 1,4-dioxane obtained in Step 2, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (520 mg, 2.02 mmol), tetrakis(triphenylphosphine)palladium (117 mg, 0.101 mmol), potassium carbonate (697 mg, 5.04 mmol) and water (3.4 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (946 mg, containing impurities).

MS: m/z 463.2 (M+H)⁺.

Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile

tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (946 mg, 1.23 mmol) was dissolved in 1,4-dioxane (5.1 mL), then to the solution, a 4 M hydrochloric acid/1,4-dioxane solution (5.1 mL) was added dropwise at 0° C., the temperature of the mixture was raised to room temperature, and the mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the concentrated crude product, and the mixture was concentrated under reduced pressure again. The mixture was vacuum dried to obtain the hydrochloride salt of the target compound (681 mg, 76%).

Exact MS: 362.2

Obs. MS (M+H)⁺: 363.3

Example 18 4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidin-1-ylpyridazin-4-yl)oxybenzonitrile (Compound No. 284)

Step 1: tert-Butyl N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazol-4-yl]ethyl]carbamate

DMA (2 mL) was added to 4-fluoro-3-phenylmethoxybenzonitrile (307 mg, 1.35 mmol), tert-butyl N-[2-(1H-pyrazol-4-yl)ethyl]carbamate (190 mg, 0.900 mmol), and potassium carbonate (373 mg, 2.70 mmol), and the mixture was stirred at 150° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (263 mg, 70%).

MS: m/z 419.2 (M+H)⁺.

Step 2: tert-Butyl N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazol-4-yl]ethyl]carbamate

tert-Butyl N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazol-4-yl]ethyl]carbamate (263 mg, 0.628 mmol) was dissolved in methanol (5 mL)/ethyl acetate (5 mL) and palladium-activated carbon (100 mg) was added to the solution under a nitrogen atmosphere. A hydrogen gas balloon was attached to the reaction vessel, and after the inside of the vessel was replaced with hydrogen gas, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (172 mg, 83%).

MS: m/z 273.0 (M-tBu+H)⁺.

Step 3: tert-Butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate

DMF (1.3 mL) was added to tert-butyl N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazol-4-yl]ethyl]carbamate (172 mg, 0.524 mmol), 3,5-dichloropyridazine (101 mg, 0.681 mmol), and potassium carbonate (217 mg, 1.57 mmol), and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (218 mg, 94%).

MS: m/z 385.0 (M-tBu+H)⁺.

Step 4: tert-Butyl N-[2-[1-[4-cyano-2-(6-pyrrolidin-1-ylpyridazin-4-yl)oxyphenyl]pyrazol-4-yl]ethyl]carbamate

tert-Butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate (70.0 mg, 0.159 mmol) was dissolved in toluene (0.8 mL), then to the solution, pyrrolidine (33.9 mg, 0.476 mmol), tris(dibenzylideneacetone)dipalladium (7.3 mg, 7.9 μmol), (±)-BINAP (9.9 mg, 16 μmol)), and cesium carbonate (220 mg, 2.25 mmol) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (51.0 mg, 68%).

Step 5: 4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidin-1-ylpyridazin-4-yl)oxybenzonitrile

tert-Butyl N-[2-[1-[4-cyano-2-(6-pyrrolidin-1-ylpyridazin-4-yl)oxyphenyl]pyrazol-4-yl]ethyl]carbamate (51.0 mg, 0.107 mmol) was dissolved in dichloromethane (2 mL), then TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (9.71 mg).

Exact MS: 375.2

Obs. MS (M+H)⁺: 376.2

Example 19 4-[5-(1-Amino-2-morpholin-4-yl-2-oxoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (Compound No. 487)

Step 1: Methyl 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate

3-(5-Cyclopropyl-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (881 mg, 2.41 mmol) synthesized in the same method as in Example 17 was dissolved in 1,4-dioxane (12 mL), then to the solution, methyl 2-(6-chloropyridin-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate (725 mg, 2.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (176.5 mg, 0.241 mmol), potassium carbonate (1.00 g, 7.24 mmol) and water (3 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (976 mg, 80%).

MS: m/z 504.4 (M+H)⁺.

Step 2: 2-[6-[4-Cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid

Methyl 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate (976 mg, 1.94 mmol) was dissolved in methanol (10 mL), then a 2 M aqueous sodium hydroxide solution (2 mL) was added to the solution, and the mixture was stirred at room temperature for 15 minutes. After adding 1 M hydrochloric acid (4 mL) to the reaction mixture and stirring the mixture, the mixture was extracted by adding ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 490.3 (M+H)⁺.

Step 3: tert-Butyl N-[1-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-morpholin-4-yl-2-oxoethyl]carbamate

An aliquot (160 mg, 0.320 mmol) of the crude product obtained in Step 2 was dissolved in DMF (1 mL), then to the solution, morpholine (0.041 mL, 0.48 mmol), HATU (160 mg, 0.420 mmol), and triethylamine (0.130 mL, 0.960 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 559.4 (M+H)⁺.

Step 4: 4-[5-(1-Amino-2-morpholin-4-yl-2-oxoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile

The crude product obtained in Step 3 was dissolved in dichloromethane (1 mL), then TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (39.7 mg).

Exact MS: 458.2

Obs. MS (M+H)⁺: 459.3

Example 20 4-[5-[(3-Aminooxetan-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 670)

Step 1: 4-Bromo-3-(6-chloro-2-methylpyrimidin-4-yl)oxybenzonitrile

4-Bromo-3-hydroxybenzonitrile (1.78 g, 9.00 mmol) was dissolved in DMSO (30 mL), then to the solution, 4,6-dichloro-2-methylpyrimidine (1.28 g, 6.0 mmol) and potassium carbonate (2.49 g, 18.0 mmol) were added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.16 g, 60%).

MS: m/z 324.0 (M+H)⁺.

Step 2: 3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzonitrile

4-Bromo-3-(6-chloro-2-methylpyrimidin-4-yl)oxybenzonitrile (325 mg, 1.00 mmol) was dissolved in DMF (5 mL), then to the solution, 7-azabicyclo[2.2.1]heptane hydrochloride (200 mg, 1.50 mmol) and potassium carbonate (415 mg, 3.00 mmol) were added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with a mixed solution of ethyl acetate/heptane (=1/1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (235 mg, 61%).

MS: m/z 385.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 7.73 (1H, d, J=8.2 Hz), 7.47 (1H, d, J=2.3 Hz), 7.36 (1H, dd, J=8.2, 1.8 Hz), 5.89 (1H, s), 4.51 (2H, brs), 2.36 (3H, s), 1.82-1.80 (4H, m), 1.57-1.50 (4H, m).

Step 3: 3-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzonitrile (231 mg, 0.600 mmol) was dissolved in 1,4-dioxane (3 mL), then to the solution, bis(pinacolato)diboron (305 mg, 1.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (43.9 mg, 0.0600 mmol), and potassium acetate (177 mg, 1.80 mmol) were added, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.

Step 4: N-[3-[[6-[2-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-cyanophenyl]pyridin-3-yl]methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide

An aliquot (64.8 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (1 mL), then to the solution, N-[3-[(6-chloropyridin-3-yl)methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide (30.3 mg, 0.100 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 mg, 0.010 mmol), potassium carbonate (41.5 mg, 0.300 mmol) and water (0.2 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.

Step 5: 4-[5-[(3-Aminooxetan-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile

The crude product obtained in Step 4 was dissolved in methanol (1 mL), then to the solution, a 4 M hydrochloric acid/1,4-dioxane solution (0.15 mL) was added at 0° C., and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (8.2 mg).

Exact MS: 468.2

Obs. MS (M+H)⁺: 469.2

Example 21 4-[5-(2-Aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]benzonitrile (Compound No. 712)

Step 1: 4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile

4-Bromo-3-fluorobenzonitrile (6.00 g, 30.0 mmol) was added to a solution of 4-methoxybenzyl alcohol (4.97 g, 36.0 mmol) and potassium tert-butoxide (4.04 g, 36.0 mmol) in DMF (100 mL), and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, the mixture was stirred, and the precipitated solid was collected by filtration through a glass filter and vacuum dried to obtain the target compound (8.04 g, 84%).

¹H-NMR (CDCl₃) δ: 7.65 (1H, d, J=7.8 Hz), 7.37 (2H, d, J=8.7 Hz), 7.13 (2H, dd, J=9.8, 1.1 Hz), 6.93 (2H, d, J=8.2 Hz), 5.11 (2H, s), 3.83 (3H, s).

Step 2: 3-[(4-Methoxyphenyl]methoxyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylbenzonitrile

4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile (1.0 g, 3.14 mmol) was dissolved in 1,4-dioxane (16 mL), then to the solution, bis(pinacolato)diboron (1.20 g, 4.71 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (115 mg, 0.157 mmol) and potassium acetate (617 mg, 6.29 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.

MS: m/z 433.2 (M+H)⁺.

Step 3: tert-Butyl N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]carbamate

tert-Butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (807 mg, 3.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (231 mg, 0.314 mmol), potassium carbonate (2.05 g, 6.29 mmol) and water (1 mL) were added to a solution of the crude product in 1,4-dioxane (6 mL) obtained in Step 2, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.17 g, 81%).

MS: m/z 460.2 (M+H)⁺.

Step 4: 4-[5-(2-Aminoethyl)pyridin-2-yl]-3-hydroxybenzonitrile

tert-Butyl N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]carbamate (1.05 g, 1.60 mmol) was dissolved in dichloromethane (10 mL), then TFA (2 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrated crude product was used in the next reaction without further purification.

Step 5: tert-Butyl N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]carbamate

The crude product obtained in Step 4 was dissolved in dichloromethane (5 mL), then to the solution, di-tert-butyl dicarbonate (698 mg, 3.20 mmol) and triethylamine (1.00 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (526 mg, 97%).

MS: m/z 340.1 (M+H)⁺.

Step 6: tert-Butyl N-[2-[6-[4-cyano-2-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]phenyl]pyridin-3-yl]ethyl]carbamate

tert-Butyl N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]carbamate (30 mg, 0.088 mmol) was dissolved in NMP (1 mL), then to the solution, 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole (24.7 mg, 0.106 mmol) and potassium carbonate (36.7 mg, 0.265 mmol) were added, and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.

MS: m/z 492.1 (M+H)⁺.

Step 7: 4-[5-(2-Aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]benzonitrile

The crude product obtained in Step 6 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (35.9 mg).

Exact MS: 391.1

Obs. MS (M+H)⁺: 392.2

Example 22 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (Compound No. 811)

Step 1: 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzonitrile

3-Fluoro-4-nitrobenzonitrile (664 mg, 4.00 mmol) and 2-methyl-5-(trifluoromethyl)-4H-pyrazol-3-one (731 mg, 4.40 mmol) were dissolved in DMF (6 mL), then potassium carbonate (663 mg, 4.80 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The obtained solid was washed with a small amount of ethyl acetate to obtain the target compound (417 mg).

MS: m/z 313.1 (M+H)⁺.

Step 2: 4-Amino-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile

Iron powder (224 mg, 4.01 mmol), ammonium chloride (214 mg, 4.01 mmol), ethanol (1.3 mL) and water (1.3 mL) were added to 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzonitrile (417 mg, 1.34 mmol), and the mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then extracted by adding ethyl acetate and water to the mother liquor. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.

MS: m/z 283.1 (M+H)⁺.

Step 3: 4-Bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile

The crude product obtained in Step 2 was dissolved in acetonitrile (6.5 mL), then isoamyl nitrite (224 mg, 1.92 mmol) and copper(II) bromide (341 mg, 1.53 mmol) were added to the solution, and the mixture was stirred at 65° C. for 16 hours. The reaction mixture was cooled to room temperature, 20% hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (389 mg).

MS: m/z 346.0 (M+H)⁺.

Step 4: 3-[2-Methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-Bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (389 mg, 1.12 mmol) was dissolved in 1,4-dioxane (5.6 mL), then to the solution, bis(pinacolato)diboron (428 mg, 1.68 mmol), bis(triphenylphosphine)palladium dichloride (78.8 mg, 0.112 mmol) and potassium acetate (220 mg, 2.25 mmol) were added, and the mixture was stirred at 110° C. for 1 hour. The reaction solution was cooled to room temperature and used in the next reaction without further purification.

MS: m/z 394.2 (M+H)⁺.

Step 5: tert-Butyl N-[[2-[4-cyano-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

tert-Butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (107 mg, 0.31 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.028 mmol), potassium carbonate (120 mg, 0.840 mmol), and water (0.3 mL) were added to an aliquot (1.2 mL) of the reaction mixture obtained in Step 4, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.

Step 6: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile

Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 5, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (88.7 mg).

Exact MS: 374.1

Obs. MS (M+H)⁺: 375.3

Example 23 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (Compound No. 875)

Step 1: 3-(5-Amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile

4-Bromo-3-fluorobenzonitrile (3.0 g, 15 mmol) and 5-amino-2-methyl-4H-pyrazol-3-one (1.7 g, 15 mmol) were dissolved in DMA (40 mL), and potassium carbonate (4.14 g, 30.0 mmol) was added to the solution, and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (444 mg, 10%).

MS: m/z 292.9 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 7.76 (1H, d, J=8.2 Hz), 7.36 (1H, d, J=1.8 Hz), 7.32 (1H, dd, J=8.0, 1.6 Hz), 5.11 (1H, s), 3.63 (2H, brs), 3.57 (3H, s).

Step 2: 4-Bromo-3-[5-(2,2-difluoroethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile

3-(5-Amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile (1.47 g, 5.00 mmol) was dissolved in DMA (10 mL), then to the solution, 1,1-difluoro-2-iodoethane (1.44 g, 7.50 mmol) and N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) were added, and the mixture was stirred at 140° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.10 g, 62%).

MS: m/z 359.0 (M+H)⁺.

Step 3: 4-Bromo-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile

4-Bromo-3-[5-(2,2-difluoroethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (1.10 g, 3.09 mmol) was dissolved in DMA (10 mL), then to the solution, iodoethane (963 mg, 6.17 mmol) and N,N-diisopropylethylamine (1.08 mL, 6.17 mmol) were added, and the mixture was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (766 mg, 64%).

MS: m/z 385.0 (M+H)⁺.

Step 4: 3-[5-[2,2-Difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-Bromo-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (766 mg, 1.99 mmol) was dissolved in 1,4-dioxane (10 mL), then to the solution, bis(pinacolato)diboron (758 mg, 2.98 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (72.8 mg, 0.0995 mmol), and potassium acetate (391 mg, 3.98 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 433.2 (M+H)⁺.

Step 5: tert-Butyl N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate

The crude product obtained in Step 4 was dissolved in 1,4-dioxane (10 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (462 mg, 1.79 mmol), tetrakis(triphenylphosphine)palladium (115 mg, 0.0995 mmol), potassium carbonate (550 mg, 3.98 mmol) and water (3 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (648 mg, 62%).

MS: m/z 528.2 (M+H)⁺.

Step 6: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile

tert-Butyl N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (648 mg, 1.23 mmol) was dissolved in 1,4-dioxane (4 mL), then a 4 M hydrochloric acid/1,4-dioxane solution (2 mL) was added dropwise at 0° C. to the mixture, then the temperature of the mixture was raised to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the solid obtained was vacuum dried to obtain a hydrochloride of the target compound (642 mg).

Exact MS: 427.2

Obs. MS (M+H)⁺: 428.3

Example 24 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 931)

Step 1: 3-(5-Amino-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

The intermediate of 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile (879 mg, 3.00 mmol) obtained in Example 23 was dissolved in 1,4-dioxane (7.5 mL), then to the solution, bis(pinacolato)diboron (1.52 g, 6.00 mmol), bis(triphenylphosphine)palladium dichloride (211 mg, 0.300 mmol), and potassium acetate (589 mg, 6.00 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.

Step 2: tert-Butyl N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

To a solution of the crude product in 1,4-dioxane (15 mL) obtained in Step 1, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.03 g, 3.00 mmol), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (220 mg, 0.300 mmol), potassium carbonate (1.24 g, 9.00 mmol), and water (3 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.48 g, containing impurities).

MS: m/z 522.3 (M+H)⁺.

Step 3: tert-Butyl N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate tert-Butyl N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.48 g, 2.83 mmol) was dissolved in acetonitrile (28 mL), then isoamyl nitrite (488 mg, 4.17 mmol) and copper(I) bromide (476 mg, 3.32 mmol) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (289 mg).

MS: m/z 585.2 (M+H)⁺.

Step 4: tert-Butyl N-[[2-[4-cyano-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

tert-Butyl N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (40 mg, 0.068 mmol) was dissolved in 1,4-dioxane (0.2 mL), then to the solution, bis(pynacolato)diboron (26.0 mg, 0.102 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (5.0 mg, 6.8 μmol) and potassium acetate (20.1 mg, 0.205 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product obtained was used in the next reaction without further purification.

Step 5: tert-Butyl N-[[2-[4-cyano-2-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

An aliquot (24 mg) of the crude product obtained in Step 4 was dissolved in 1,4-dioxane (0.19 mL), then to the solution, 2-chloropyrazine (25.7 mg, 0.076 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (2.8 mg, 3.8 μmol), potassium carbonate (16 mg, 0.11 mmol) and water (0.038 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 6: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzonitrile

TFA (0.5 mL) was added to the crude product obtained in Step 5, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.25 mg).

Exact MS: 384.1

Obs. MS (M+H)⁺: 385.2

Example 25 2-[2-[4-Fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Compound No. 966) (Target compound) and 2-[2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Compound No. 967) (Regioisomer)

Step 1: 1-(2-Bromo-5-fluorophenoxy)propan-2-one

2-Bromo-5-fluorophenol (2.29 g, 12.0 mmol) and 1-bromopropan-2-one (1.97 g, 14.4 mmol) were dissolved in DMF (20 mL), potassium carbonate (3.32 g, 24.0 mmol) was added to the solution, and the mixture was heated and stirred at 100° C. After completion of the reaction, the reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.51 g, 85%).

Step 2: 3-(2-Bromo-5-fluorophenoxy)-4-(dimethylamino)but-3-en-2-one

To 1-(2-bromo-5-fluorophenoxy)propan-2-one (2.73 g, 11.0 mmol), N,N-dimethylformamide dimethylacetal (1.58 g, 13.2 mmol) was added, the mixture was stirred at 80° C. overnight. After cooling the reaction mixture to room temperature, acetic acid (20 mL) and hydrazine monohydrate (826 mg, 16.5 mmol) were added to the mixture, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.41 g, 81%).

MS: m/z 271.0 (M+H)⁺.

Step 3: 4-(2-Bromo-5-fluorophenoxy)-3-methyl-1-(2-methylpropyl)pyrazole

To 4-(2-bromo-5-fluorophenoxy)-3-methyl-1H-pyrazole (270 mg, 1.0 mmol), DMSO (2 mL), 1-bromo-2-methylpropane (160 mg, 1.2 mmol), and potassium carbonate (280 mg, 2.0 mmol) were added, and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a mixture (185 mg) of the target compound and its regioisomer. Regioisomers were separated by HPLC purification after the last step.

MS: m/z 327.1 (M+H)⁺.

¹H-NMR (DMSO-d₆) δ: 7.80 (1H, s), 7.72 (1H, dd, J=9.2, 2.8 Hz), 6.93-6.88 (I H, m), 6.60 (1H, dd, J=10.4, 2.8 Hz), 3.81 (1H, d, J=7.2 Hz), 2.14-2.07 (1H, m), 1.98 (3H, s), 0.85 (6H, d, J=6.8 Hz).

Step 4: 4-[5-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy]-3-methyl-1-(2-methylpropyl)pyrazole

The isomer mixture (185 mg, 0.565 mmol) obtained in Step 3 was dissolved in 1,4-dioxane (1.1 mL), then to the solution, bis(pinacolato)diboron (215 mg, 0.848 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (20.7 mg, 0.0283 mmol) and potassium acetate (111 mg, 1.13 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 5: tert-Butyl N-[2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate

An aliquot (106 mg) of the crude product obtained in Step 4 was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (87.6 mg, 0.340 mmol), tetrakis(triphenylphosphine)palladium (16.4 mg, 0.0142 mmol), potassium carbonate (78.3 mg, 0.566 mmol), and water (0.3 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 6: 2-[2-[4-Fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Target compound) and 2-[2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Regioisomer)

The crude product obtained in Step 5 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (11.82 mg) and its regioisomer (10.77 mg).

Exact MS: 369.2

Obs. MS (M+H)⁺: 370.4 (Compound No. 966), 370.3 (Compound No. 967)

Example 26 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (Compound No. 1028)

Step 1: 4-Chloro-3-[hydroxy-(2-methyl-5-nitropyrazol-3-yl)methyl]benzonitrile

3-Bromo-4-chlorobenzonitrile (5.69 g, 26.3 mmol) was dissolved in THF (50 mL), then to the solution, isopropylmagnesium chloride lithium chloride complex (14% solution in THF, 20 mL, 26.27 mmol) was added dropwise at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A solution (5 mL) of 2-methyl-5-nitropyrazole-3-carbaldehyde (3.13 g, 20.2 mmol) in THF was added dropwise to this reaction mixture, the temperature of the mixture was raised to room temperature, and the mixture was stirred for 1 hour. 1 M hydrochloric acid was added to the reaction mixture, the mixture was stirred, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (4.85 g, 82%).

MS: m/z 293.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 8.06 (1H, s), 7.67 (1H, dd, J=8.2, 1.8 Hz), 7.56 (1H, d, J=8.2 Hz), 6.39 (1H, s), 6.23 (1H, s), 4.10 (3H, s), 2.97 (1H, s).

Step 2: 4-Chloro-3-(2-methyl-5-nitropyrazole-3-carbonyl)benzonitrile

Dess-Martin reagent (7.73 g, 18.2 mmol) was added to a solution (83 mL) of 4-chloro-3-[hydroxy-(2-methyl-5-nitropyrazol-3-yl)methyl]benzonitrile (4.85 g, 16.6 mmol) in dichloromethane, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 291.0 (M+H)⁺.

¹H-NMR (DMSO-d₆) δ: 8.21 (1H, d, J=2.3 Hz), 8.11 (1H, dd, J=8.5, 2.1 Hz), 7.88 (1H, d, J=8.2 Hz), 7.58 (1H, s), 4.27 (3H, s).

Step 3: 3-(5-Amino-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile

The crude product obtained in Step 2 was suspended in a mixed solvent (66 mL) of ethanol/water (=1/1), then to the suspension, iron powder (2.78 g, 49.7 mmol) and ammonium chloride (2.66 g, 49.74 mol) were added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then most of the ethanol was evaporated under reduced pressure. The residue was extracted by adding ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (3.76 g, 87%).

MS: m/z 261.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 7.72-7.70 (2H, m), 7.60 (1H, d, J=9.1 Hz), 5.67 (1H, s), 4.11 (3H, s), 3.73 (2H, brs).

Step 4: 4-Chloro-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile

3-(5-Amino-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile (449 mg, 1.72 mmol) was dissolved in NMP (4.3 mL), then to the solution, bis(2-bromoethyl)ether (439 mg, 1.89 mmol) and potassium iodide (28.6 mg, 0.172 mmol) were added, and the mixture was stirred at 110° C. for 16 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (391 mg, 69%).

MS: m/z 331.1 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 7.73-7.71 (2H, m), 7.61 (1H, dd, J=7.5, 1.6 Hz), 5.68 (1H, s), 4.15 (3H, s), 3.80 (4H, t, J=4.8 Hz), 3.14 (4H, t, J=4.8 Hz).

Step 5: 3-(2-Methyl-5-morpholin-4-ylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-Chloro-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (391 mg, 1.18 mmol) was dissolved in 1,4-dioxane (4 mL), then to the solution, bis(pinacolato)diboron (451 mg, 1.78 mmol), bis(tricyclohexylphosphine)palladium dichloride (87.3 mg, 0.118 mmol) and potassium acetate (348 mg, 3.55 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 423.2 (M+H)⁺.

Step 6: tert-Butyl N-[[2-[4-cyano-2-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)phenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

An aliquot (166 mg) of the crude product obtained in Step 5 was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (50.0 mg, 0.145 mmol), tetrakis(triphenylphosphine)palladium (16.8 mg, 0.0145 mmol), potassium carbonate (60.3 mg, 0.436 mmol), and water (0.1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 604.3 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 8.70 (2H, s), 8.51 (1H, d, J=8.2 Hz), 7.90 (1H, d, J=8.2 Hz), 7.79 (1H, s), 5.38 (1H, S), 4.73 (2H, s), 4.14 (3H, s), 3.72 (4H, t, J=4.8 Hz), 3.00 (4H, t, J=4.8 Hz), 1.48 (18H, s).

Step 7: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 6, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (34.2 mg).

Exact MS: 403.2

Obs. MS (M+H)⁺: 404.3 ¹H-NMR (DMSO-d₆) δ: 8.93 (2H, s), 8.49 (1H, d, J=7.8 Hz), 8.32 (3H, brs), 8.18 (1H, dd, J=8.2, 1.8 Hz), 8.10 (1H, d, J=1.8H), 5.72 (1H, S), 4.10 (2H, d, J=5.9 Hz), 4.02 (3H, S), 3.57 (4H, t, J=4.8 Hz), 2.92 (4H, t, J=4.6 Hz).

Example 27 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (Compound No. 1030)

Step 1: 3-[(5-tert-Butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile

3-Bromo-4-chlorobenzonitrile (3.28 g, 15.2 mmol) was dissolved in THF (50 mL), and isopropylmagnesium chloride lithium chloride complex (14% solution in THF, 13 mL, 16.7 mmol) was added dropwise to the solution at 0° C., and the mixture was stirred at the same temperature for 15 minutes. A solution (5 mL) of 5-tert-butyl-2-methylpyrazole-3-carbaldehyde (2.52 g, 15.2 mmol) in THF was added dropwise to the reaction solution, then the temperature of the mixture was raised to room temperature, and the mixture was stirred for 1.5 hours. 1 M Hydrochloric acid was added to the reaction mixture, the mixture was stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethanol was added to the crude product, the mixture was stirred, and then the precipitated solid was collected by filtration through a glass filter, and vacuum dried to obtain the target compound (2.22 g, 48%).

MS: m/z 304.2 (M+H)⁺.

¹H-NMR (CDCl₃) δ: 8.02 (1H, d, J=1.8 Hz), 7.60 (1H, dd, J=8.2, 1.8 Hz), 7.49 (1H, d, J=8.2 Hz), 6.15 (1H, d, J=5.0 Hz), 5.62 (1H, s), 3.90 (3H, s), 2.49 (1H, d, J=5.0 Hz), 1.23 (9H, s).

Step 2: 3-(5-tert-Butyl-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile

Dess-Martin reagent (768 mg, 1.81 mmol) was added to a solution (16 mL) of 3-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile (500 mg, 1.65 mmol) in dichloromethane, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (440 mg, 89%).

MS: m/z 302.1 (M+H)⁺.

Step 3: 3-(5-tert-Butyl-2-methylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-(5-tert-Butyl-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile (440 mg, 1.46 mmol) was dissolved in 1,4-dioxane (4.9 mL), then to the solution, bis(pinacolato)diboron (556 mg, 2.19 mmol), bis(tricyclohexylphosphine)palladium dichloride (53.9 mg, 0.073 mmol) and potassium acetate (430 mg, 4.38 mmol) were added, and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 394.3 (M+H)⁺.

Step 4: tert-Butyl N-[[2-[2-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

An aliquot (115 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (50.0 mg, 0.145 mmol), tetrakis(triphenylphosphine)palladium (16.8 mg, 0.0145 mmol), potassium carbonate (60.3 mg, 0.436 mmol), and water (0.1 mL) was added, and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 575.4 (M+H)⁺.

Step 5: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (9.7 mg).

Exact MS: 374.2

Obs. MS (M+H)⁺: 375.4

Example 28 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (Compound No. 1042)

Step 1: N-Methoxy-N,2-dimethyl-6-morpholin-4-ylpyridine-4-carboxamide

2-Methyl-6-morpholin-4-ylpyridine-4-carboxylic acid (235 mg, 1.43 mmol) was dissolved in DMF (5.3 mL), then to the solution, N,O-dimethylhydroxylamine hydrochloride (124 mg, 1.27 mmol), HATU (524 mg, 1.38 mmol) and triethylamine (0.45 mL, 3.18 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solution was concentrated under reduced pressure. Then, the crude product was purified by silica gel column chromatography to obtain the target compound (174 mg, 62%).

MS: m/z 266.1 (M+H)⁺.

Step 2: 4-Chloro-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile

3-Bromo-4-chlorobenzonitrile (284 g, 1.31 mmol) was dissolved in THF (3.3 mL), and isopropylmagnesium chloride lithium chloride complex (14% solution in THF, 1.0 mL, 1.31 mmol) was added dropwise to the solution at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A solution (1 mL) of N-methoxy-N,2-dimethyl-6-morpholin-4-ylpyridine-4-carboxamide (174 mg, 0.656 mmol) in THF was added dropwise to the reaction mixture, and then the temperature of the mixture was raised to room temperature, and the mixture was stirred for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (67.1 mg, 30%).

MS: m/z 342.1 (M+H)⁺.

Step 3: 3-(2-Methyl-6-morpholin-4-ylpyridine-4-carbonyl)-4-trimethylstannylbenzonitrile

4-Chloro-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (67.1 mg, 0.196 mmol) was dissolved in 1,4-dioxane (1 mL), then to the solution, hexamethylditin (96.5 mg, 0.294 mmol) and tetrakis(triphenylphosphine)palladium (22.7 mg, 0.0196 mmol) were added, and the mixture was stirred at 110° C. for 3 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (21.3 mg, 23%).

MS: m/z 472.1 (M+H)⁺.

Step 4: tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)phenyl]pyrimidin-5-yl]ethyl]carbamate

3-(2-Methyl-6-morpholin-4-ylpyridine-4-carbonyl)-4-trimethylstannylbenzonitrile (21.3 mg, 0.0453 mmol) was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (30.0 mg, 0.116 mmol), tetrakis(triphenylphosphine)palladium (5.2 mg, 4.53 μmol), and copper(I) iodide (1.7 mg, 9.06 μmol) was added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 529.3 (M+H)⁺.

Step 5: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile

Dichloromethane (1.0 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.0 mg, 26%).

Exact MS: 428.2

Obs. MS ((M+H)⁺: 429.3

Example 29 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile (Compound No. 1064)

Step 1: 4-Chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]benzonitrile

4-(4-Methyl-1,3-thiazol-2-yl)morpholine (1.25 g, 6.78 mmol) was dissolved in THF (34 mL), the solution was cooled to −78° C., then to the solution, an n-butyllithium hexane solution (2.76 M, 2.7 mL, 7.46 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 4-chloro-3-formylbenzonitrile (1.24 g, 7.46 mmol) was added, and the mixture was stirred at −78° C. for 1 hour. Then, the temperature of the mixture was raised to room temperature, a saturated aqueous ammonium chloride solution was added to the mixture, the mixture was stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.30 g, 55%).

MS: m/z 350.0 (M+H)⁺.

Step 2: 4-Chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile

4-Chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]benzonitrile (500 mg, 1.43 mmol) was dissolved in THF (15 mL), then to the solution, 2-iodoxybenzoic acid (801 mg, 2.86 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, a saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. Then, the crude product was purified by silica gel column chromatography to obtain the target compound (310 mg, 62%).

MS: m/z 348.0 (M+H)⁺.

Step 3: 3-(4-Methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)-4-trimethylstannylbenzonitrile

4-Chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile (170 mg, 0.489 mmol) was dissolved in 1,4-dioxane (1.2 mL), then to the solution, hexamethylditin (240 mg, 0.733 mmol) and tetrakis(triphenylphosphine)palladium (56.5 mg, 0.0489 mmol) were added, and the mixture was stirred at 110° C. for 4 hours. The reaction mixture was cooled to room temperature and purified directly by silica gel column chromatography to obtain the target compound (138 mg, 59%).

MS: m/z 478.0 (M+H)⁺.

Step 4: tert-Butyl N-[[2-[4-cyano-2-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)phenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate

3-(4-Methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)-4-trimethylstannylbenzonitrile (46.0 mg, 0.0966 mmol) was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (66.0 mg, 0.193 mmol), tetrakis(triphenylphosphine)palladium (11.2 mg, 9.66 μmol) and copper(I) iodide (3.68 mg, 0.0193 mmol) were added, and the mixture was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

Step 5: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile

Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (10.8 mg).

Exact MS: 420.1

Obs. MS (M+H)⁺: 421.2

Example 30 4-[5-(2-Aminoethyl)pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile (Compound No. 1131)

Step 1: 3-[(4-Phenylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (6.00 g, 18.6 mmol) was dissolved in DMF (80 mL), then to the solution, 4-phenyl-1H-imidazole (2.69 g, 18.6 mmol) and potassium carbonate (5.15 g, 37.3 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.

MS: m/z 386.2 (M+H)⁺.

Step 2: tert-Butyl N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]carbamate

The crude product obtained in Step 1 was dissolved in 1,4-dioxane (80 mL), then to the solution, tert-butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (3.87 g, 15.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (552 mg, 0.754 mmol), potassium carbonate (4.17 g, 30.2 mmol) and water (20 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.41 g, 20%).

MS: m/z 480.2 (M+H)⁺.

Step 3: 4-[5-(2-Aminoethyl(pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile

1,4-Dioxane (20 mL) was added to tert-butyl N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]carbamate (1.19 g, 2.49 mmol), then to the mixture, a 4 M hydrochloric acid/dioxane solution (20 mL) was added dropwise at 0° C., the temperature of the mixture was raised to room temperature, and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (678 mg, 72%).

Exact MS: 379.2

Obs. MS (M+H)⁺: 380.3

Example 31 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzonitrile (Compound No. 1179)

Step 1: 3-[(4-Formyl-2-methylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (354 mg, 1.10 mmol) was dissolved in acetonitrile (5 mL), then to the solution, 2-methyl-1H-imidazole-4-carbaldehyde (110 mg, 1.00 mmol) and triethylamine (0.356 mL, 2.00 mmol) were added, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction without further purification.

Step 2: tert-Butyl N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate

The crude product obtained in Step 1 was dissolved in 1,4-dioxane (5 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (283 mg, 1.10 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (73.4 mg, 0.100 mmol), potassium carbonate (415 mg, 3.00 mmol) and water (1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (446 mg, quant.).

MS: m/z 447.3 (M+H)⁺.

Step 3: tert-Butyl N-[2-[2-[4-cyano-2-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate

tert-Butyl N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (31.0 mg, 0.070 mmol) was dissolved in dichloromethane (0.7 mL), then to the solution, piperidine (7.2 mg, 0.084 mmol) and sodium triacetoxyborohydride (37.0 mg, 0.180 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.

Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzonitrile

Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (12.2 mg).

Exact MS: 415.3

Obs. MS (M+H)⁺: 416.4

Example 32 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile (Compound No. 1187)

Step 1: 3-(Azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.50 g, 10.9 mmol) was dissolved in DMSO (22 mL), then to the solution, sodium azide (777 mg, 12.0 mmol) was added, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.80 g, 91%).

Step 2: 3-[(4-Cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-(Azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.10 g, 3.87 mmol) was dissolve in DMSO (10 mL), then to the solution, ethynylcyclopropane (307 mg, 4.65 mmol), copper(I) iodide (36.9 mg, 0.194 mmol) and TBTA (103 mg, 0.194 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (416 mg, 31%).

Step 3: tert-Butyl N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate

3-[(4-Cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (208 mg, 0.594 mmol) was dissolved in 1,4-dioxane (3 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (168 mg, 0.653 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 0.030 mmol), sodium carbonate (126 mg, 1.19 mmol) and water (1 mL) were added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (120 mg, 45%).

Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to tert-butyl N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (120 mg, 0.269 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (12.8 mg).

Exact MS: 345.2

Obs. MS (M+H)⁺: 346.2

Example 33 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[I-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile (Compound No. 1195)

Step 1: 1-(2-Methylpropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.94 g, 10.0 mmol) was dissolved in DMF (10 mL), then to the solution, 1-bromo-2-methylpropane (1.64 g, 12.0 mmol) and potassium carbonate (4.14 g, 30.0 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.

MS: m/z 251.2 (M+H)⁺.

Step 2: 4-Chloro-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile

An aliquot (500 mg, 2.00 mmol) of the crude product obtained in Step 1 was dissolved in 1,4-dioxane (10 mL), then to the solution, 3-(bromomethyl)-4-chlorobenzonitrile (461 mg, 2.00 mmol), tetrakis(triphenylphosphine)palladium (162 mg, 0.140 mmol), cesium carbonate (1.95 g, 6.00 mmol) and water (2 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (548 mg, containing impurities).

MS: m/z 274.1 (M+H)⁺.

Step 3: 3-[[1-(2-Methylpropyl)pyrazol-4-yl]methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

4-Chloro-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile (274 mg, 1.00 mmol) was dissolved in 1,4-dioxane (3.3 mL), then to the solution, bis(pinacolato)diboron (381 mg, 1.50 mmol), bis(tricyclohexylphosphine)palladium dichloride (73.8 mg, 0.100 mmol), and potassium acetate (294 mg, 3.00 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 366.3 (M+H)⁺.

Step 4: tert-Butyl N-[2-[2-[4-cyano-2-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate

An aliquot (37 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (0.5 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (25.8 mg, 0.100 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 mg, 0.01 mmol), potassium carbonate (41.0 mg, 0.300 mmol), and water (0.1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

Step 5: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile

TFA (0.5 mL) was added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (26.0 mg).

Exact MS: 360.2

Obs. MS (M+H)⁺: 361.0

Example 34 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]benzonitrile (Compound No. 1198)

Step 1: 3-[(4-Nitropyrazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (230 mg, 0.700 mmol) was dissolved in DMF (0.7 mL), then to the solution, 4-nitro-1H-pyrazole (95 mg, 0.84 mmol) and potassium carbonate (190 mg, 1.40 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product was used in the next reaction without further purification.

MS: m/z 355.2 (M+H)⁺.

Step 2: tert-Butyl N-[2-[2-[4-cyano-2-[(4-nitropyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate

The crude product obtained in Step 1 was dissolved in 1,4-dioxane (3.5 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (180 mg, 0.700 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (51.2 mg, 0.0700 mmol), potassium carbonate (290 mg, 2.10 mmol), and water (0.7 mL) were added, and the mixture was stirred at 100° C. for 1 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (310 mg, 99%).

MS: m/z 450.2 (M+H)⁺.

Step 3: tert-Butyl N-[2-[2-[2-[(4-aminopyrazol-1-yl)methyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate

tert-Butyl N-[2-[2-[4-cyano-2-[(4-nitropyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (310 mg, 0.690 mmol) was dissolved in methanol (0.7 mL) and palladium-active carbon ethylenediamine complex (50 mg) was added to the mixture. A hydrogen gas balloon was attached to the reaction vessel, and after the inside of the vessel was replaced with hydrogen gas, the mixture was stirred at room temperature overnight. After filtering the reaction mixture with Celite, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

MS: m/z 420.3 (M+H)⁺.

Step 4: tert-Butyl N-[2-[2-[4-cyano-2-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate

An aliquot (45.2 mg) of the crude product obtained in Step 3 was dissolved in DMA (0.5 mL), then to the solution, 1,4-dibromobutane (25.6 mg, 0.119 mmol) and N,N-diisopropylethylamine (0.054 mL, 0.323 mmol) were added, and the mixture was stirred at 110° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 474.3 (M+H)⁺.

Step 5: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]benzonitrile

TFA (0.5 mL) was added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (7.4 mg).

Exact MS: 373.2

Obs. MS (M+H)⁺: 374.2

Example 35 4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)ethyl]benzonitrile (Compound No. 1226))

Step 1: tert-Butyl (2-(2′-acetyl-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate

To a mixed solution (5 mL) of 2-acetyl-4-cyanophenyltrifluoromethanesulfonate (250 mg, 0.85 mmol) in toluene/water (=4/1), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (355 mg, 1.02 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (62.4 mg, 0.085 mmol), and potassium carbonate (354 mg, 2.56 mmol) were added, and the mixture was stirred at 110° C. for 30 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added to the mixture. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (328 mg, quant.).

MS: m/z 309.1 (M+H-tBu)⁺.

Step 2: tert-Butyl (2-(4′-cyano-2′-(1-(2-tosylhydrazono)ethyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate

p-Toluene sulfonyl hydrazide (167 mg, 0.899 mmol) was added to a solution (3 mL) of tert-butyl (2-(2′-acetyl-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate (328 mg, 0.899 mmol) in toluene, and the mixture was stirred at 110° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

MS: m/z 477.2 (M+H-tBu)⁺.

Step 3: tert-Butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1′-biphenyl]-4-ylethylcarbamate

The crude product obtained in Step 2 was dissolved in 1,4-dioxane (4.5 mL), then to the solution, 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (192 mg, 0.899 mmol), tris(dibenzylideneacetone)dipalladium (32.9 mg, 0.036 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (68.6 mg, 0.14 mmol) and lithium tert-butoxide (166 mg, 2.07 mmol) were added, and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (96.1 mg, 20%).

MS: m/z 526.3 (M+H)⁺.

Step 4: tert-Butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)ethyl)-[1,1′-biphenyl]-4-yl)ethyl carbamate

Ethyl acetate (4 mL) was added to tert-butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate (79 mg, 0.15 mmol), and 10% palladium-activated carbon (20 mg) was added to the mixture under a nitrogen atmosphere. A hydrogen gas balloon was attached to the reaction vessel, the inside of the vessel was replaced with hydrogen gas, and the mixture was stirred at room temperature for 1 hour. After replacing the reaction system with nitrogen, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.

MS: m/z 528.3 (M+H)⁺.

Step 5: 4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)ethyl]benzonitrile

The crude product obtained in Step 4 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (30.8 mg).

Exact MS: 427.2

Obs. MS (M+H)⁺: 428.5

Example 36 4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]benzonitrile (Compound No. 1227)

Step 1: tert-Butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate

DMSO (0.5 mL) and sodium hydride (1.3 mg) were added to trimethyl sulfoxonium iodide (7.1 mg, 0.032 mmol), the mixture was stirred at room temperature for 40 minutes, then to the mixture, a solution (0.5 mL) of tert-butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate (16.9 mg, 0.032 mmol) in DMSO obtained in Example 35 was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 540.3 (M+H)⁺.

Step 2: 4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]benzonitrile

The crude product obtained in Step 1 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (11.6 mg).

Exact MS: 439.2

Obs. MS (M+H)⁺: 440.5

Example 37 4-[4-(2-Aminoethyl)phenyl]-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile (Compound No. 1232)

Step 1: 4-Bromo-3-(1-hydroxyprop-2-ynyl)benzonitrile

THF (40 mL) was added to 4-bromo-3-formylbenzonitrile (1.38 g, 6.57 mmol), then to the mixture, a 0.5 M ethynylmagnesium bromide solution (14.5 mL, 7.23 mmol) in THF was added dropwise at 0° C., and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, 2 M hydrochloric acid was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.

Step 2: 4-Bromo-3-[hydroxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile

To an aliquot (283 mg) of the crude product obtained in Step 1, (2Z)—N-hydroxy-1,3-thiazole-2-carboximidoyl chloride (163 mg, 1.00 mmol), potassium carbonate (276 mg, 2.00 mmol) and toluene (1 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (65.6 mg, 18%).

MS: m/z 362.0 (M+H)⁺.

Step 3: 4-Bromo-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile

4-Bromo-3-[hydroxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile (65.6 mg, 0.181 mmol) was dissolved in DMF (1 mL), then sodium hydride (9.5 mg, 0.217 mmol) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. Iodomethane (38.8 mg, 0.272 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.

MS: m/z 377.9 (M+H)⁺.

Step 4: tert-Butyl N-[2-[4-[4-cyano-2-[methoxy-[3-(1,3-thiazol-2-yl-1,2-oxazol-5-yl]methyl]phenyl]phenyl]ethyl]carbamate

The crude product obtained in Step 3 was dissolved in 1,4-dioxane (0.8 mL), then to the solution, tert-butyl N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (75.4 mg, 0.217 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (6.6 mg, 9.0 μmol), potassium carbonate (50.0 mg, 0.362 mmol) and water (0.2 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

MS: m/z 517.2 (M+H)⁺.

Step 5: 4-[4-(2-aminoethyl)phenyl]-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (48.3 mg).

Exact MS: 416.1

Obs. MS (M+H)⁺: 417.2

Example 38 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]benzonitrile (Compound No. 1237)

Step 1: tert-Butyl N-[2-[2-[2-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate

THF (7.8 mL) was added to tert-butyl N-[2-[2-[2-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate (379 mg, 0.776 mmol), which can be synthesized in the same method as in Example 27, and a 4 M lithium borohydride solution (0.776 mL, 2.33 mmol) in THF was added dropwise to the mixture. After stirring the mixture at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.

MS: m/z 491.3 (M+H)⁺.

Step 2: tert-Butyl N-[2-[2-[2-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate

An aliquot (127 mg) of the crude product obtained in Step 1 was dissolved in DMF (1 mL), then to the solution, chloroacetonitrile (23.4 mg, 0.310 mmol) and cesium carbonate (169 mg, 0.517 mmol) were added, and the mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.

MS: m/z 530.3 (M+H)⁺.

Step 3: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]benzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (10.2 mg).

Exact MS: 429.2

Obs. MS (M+H)⁺: 430.2

Example 39 4-[4-(2-Aminoethyl)phenyl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile (Compound No. 1240)

Step 1: [5-Cyano-2-[5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyridin-2-yl]phenyl]trifluoromethanesulfonate

Dichloromethane (5 mL), and pyridine (172 mg, 2.17 mmol) were added to the intermediate of tert-butyl N-[2-[4-(4-cyano-2-hydroxyphenyl)phenyl]ethyl]carbamate (245 mg, 0.724 mmol) obtained in Example 6, the mixture was cooled to 0° C., and trifluoromethanesulfonic anhydride (306 mg, 1.09 mmol) was added dropwise to the mixture. After stirring the mixture at the same temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (301 mg, 88%).

MS: m/z 415.0 (M-tBu+H)⁺.

Step 2: 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]phenyl]phenyl]sulfanylpropanoate

[5-Cyano-2-[5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyridin-2-yl]phenyl]trifluoromethanesulfonate (301 mg, 0.640 mmol) was dissolved in 1,4-dioxane (2.6 mL), then to the solution, 2-ethylhexyl 3-mercaptopropionate (168 mg, 0.768 mmol), tris(dibenzylideneacetone)dipalladium (29 mg, 0.032 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0.064 mmol) and N,N-diisopropylethylamine (0.223 mL, 1.28 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (479 mg, containing impurities).

MS: m/z 439.2 (M-Boc+H)⁺.

Step 3: tert-Butyl N-[2-[4-[2-(6-chloropyridazin-4-ylsulfanyl-4-cyanophenyl]phenyl]ethyl]carbamate

2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]phenyl]phenyl]sulfanylpropanoate (479 mg) was dissolved in DMF (5 mL), then to the solution, 3,5-dichloropyridazine (265 mg, 1.78 mmol) and DBU (0.5 mL) were added, and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (340 mg).

MS: m/z 411.0 (M-tBu+H)⁺.

¹H-NMR (CDCl₃) δ: 8.58 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=1.4 Hz), 7.86 (1H, dd, J=8.0, 1.6 Hz), 7.61 (1H, d, J=7.8 Hz), 7.22-7.17 (4H, m), 6.83 (1H, d, J=2.3 Hz), 4.65 (1H, brs), 3.36 (2H, q, J=6.6 Hz), 2.80 (2H, t, J=6.9 Hz), 1.45 (9H, s).

Step 4: tert-Butyl N-[2-[4-[4-cyano-2-(6-piperidin-1-ylpyridazin-4-yl)sulfanylphenyl]phenyl]ethyl]carbamate

DMF (1 mL) was added to tert-butyl N-[2-[4-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]phenyl]ethyl]carbamate (50.0 mg, 0.107 mmol), then to the solution, piperidine (27.4 mg, 0.321 mmol) and N,N-diisopropylethylamine (0.15 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

Step 5: 4-[4-(2-Aminoethyl)phenyl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (41.7 mg).

Exact MS: 415.2

Obs. MS (M+H)⁺: 416.4

Example 40 4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile (Compound No. 1246)

Step 1: tert-Butyl N-[2-[1-(2-bromo-4-cyanophenyl)pyrazol-4-yl]ethyl]carbamate

DMF (15 mL) was added to 3-bromo-4-fluorobenzonitrile (1.80 g, 9.00 mmol), tert-butyl N-[2-(1H-pyrazol-4-yl)ethyl]carbamate (950 mg, 4.50 mmol) and potassium carbonate (1.87 g, 13.5 mmol), and the mixture was stirred at 150° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.86 g, containing impurities).

MS: m/z 391.0 (M+H)⁺.

Step 2: 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyrazol-1-yl]phenyl]sulfanylpropanoate

tert-Butyl N-[2-[1-(2-bromo-4-cyanophenyl)pyrazol-4-yl]ethyl]carbamate (500 mg, 1.28 mmol) was dissolved in 1,4-dioxane (5.11 mL), then to the solution, 2-ethylhexyl 3-mercaptopropionate (335 mg, 1.53 mmol), tris(dibenzylideneacetone)dipalladium (58.5 mg, 0.0639 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73.9 mg, 0.128 mmol) and N,N-diisopropylethylamine (0.445 mL, 2.56 mmol) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (723 mg, 96%).

MS: m/z 529.3 (M+H)⁺.

Step 3: tert-Butyl N-[2-[l-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate

2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyrazol-1-yl]phenyl]sulfanylpropanoate (723 mg, 1.37 mmol) was dissolved in DMF (2 mL), then to the solution, 3,5-dichloropyridazine (408 mg, 2.74 mmol) and DBU (0.5 mL) were added, and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (543 mg, 87%).

MS: m/z 401.1 (M-tBu+H)⁺.

¹H-NMR (CDCl₃) δ: 8.78 (1H, d, J=1.8 Hz), 7.95 (1H, d, J=1.8 Hz), 7.88 (1H, dd, J=8.5, 2.1 Hz), 7.77 (1H, d, J=8.2 Hz), 7.72 (1H, s), 7.52 (1H, s), 7.00 (1H, d, J=1.8 Hz), 4.61 (1H, brs), 3.29 (2H, q, J=6.6 Hz), 2.66 (2H, t, J=7.1 Hz), 1.44 (9H, s).

Step 4: tert-Butyl N-[2-[1-[4-cyano-2-(6-piperidin-1-ylpyridazin-4-yl)sulfanylphenyl]pyrazol-4-yl]ethyl]carbamate

DMF (1 mL) was added to tert-butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate (60 mg, 0.131 mmol), then to the mixture, piperidine (33.5 mg, 0.394 mmol) and N,N-diisopropylethylamine (0.15 mL) were added, and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.

Step 5: 4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (50.3 mg, 95%).

Exact MS: 405.2

Obs. MS (M+H)⁺: 406.4

Example 41 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfinylbenzonitrile (Compound No. 1276)

Step 1: tert-Butyl N-[2-[2-[2-(6-chloropyridazin-4-yl)sulfinyl-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate

Dichloromethane (3.3 mL) was added to tert-butyl N-[2-[2-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate (154 mg, 0.328 mmol), then to the mixture, 3-chloroperbenzoic acid (75.4 mg, 0.328 mmol) was added at 0° C., and then the reaction mixture was heated to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product obtained was used in the next reaction.

MS: m/z 485.1 (M+H)⁺.

Step 2: tert-Butyl N-[2-[2-[4-cyano-2-(6-piperidin-1-ylpyridazin-4-yl)sulfinylphenyl]pyrimidin-5-yl]ethyl]carbamate

An aliquot (79.1 mg) of the crude product obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), then to the solution, piperidine (27.8 mg, 0.326 mmol), tris(dibenzylideneacetone)dipalladium (14.9 mg, 0.0163 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18.9 mg, 0.0326 mmol), and cesium carbonate (159 mg, 0.489 mmol) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude was used in the next reaction.

MS: m/z 534.2 (M+H)⁺.

Step 3: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfinylbenzonitrile

Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (1.72 mg).

Exact MS: 433.2

Obs. MS (M+H)⁺: 434.3

Example 42 5-[5-(2-Aminoethyl)pyridin-2-yl]-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile (Compound No. 1277)

Step 1: 5-Bromo-2-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine

5-Bromo-2,4-dichloropyridine (230 mug, 1.00 mmol) and 2-methyl-5-phenyl-4H-pyrazol-3-one (170 mg, 1.00 mmol) were dissolved in NMP (4 mL), then to the solution, potassium carbonate (280 mg, 2.00 mmol) was added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (279 mg, 77%).

MS: m/z 364.0 (M+H)⁺.

Step 2: tert-Butyl N-[2-[6-[6-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate

tert-Butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (77 mg, 0.30 mmol) was dissolved in 1,4-dioxane (1.5 mL), then to the solution, hexamethylditin (128 mg, 0.390 mmol) and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 1.5 hours. To the reaction mixture, 5-bromo-2-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine (109 mg, 0.300 mmol) and copper(I) iodide (5.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (47.2 mg, 31%).

MS: m/z 506.2 (M+H)⁺.

Step 3: tert-Butyl N-[2-[6-[6-cyano-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate

tert-Butyl N-[2-[6-[6-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate (32.2 mg, 0.0636 mmol) was dissolved in DMF (0.13 mL), then to the solution, zinc cyanide (4.5 mg, 0.038 mmol), zinc powder (0.4 mg, 6.4 μmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride-dichloromethane adduct (2.6 mg, 3.2 μmol) were added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 4: 5-[5-(2-Aminoethyl)pyridin-2-yl]-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile

Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (3.6 mg).

Exact MS: 396.2

Obs. MS (M+H)⁺: 397.2

Example 43 5-[5-(2-Aminoethyl)pyridin-2-yl]-6-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile (Compound No. 1279)

Step 1: 3-Bromo-6-chloro-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine

3-Bromo-6-chloro-2-fluoropyridine (420 mg, 2.00 mmol) and 2-methyl-5-phenyl-4H-pyrazol-3-one (348 mg, 2.00 mmol) were dissolved in NMP (8 mL), then to the solution, potassium carbonate (552 mg, 3.99 mmol) was added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (495 mg, 68%).

MS: m/z 364.0 (M+H)⁺.

Step 2: tert-Butyl N-[2-[6-[6-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate

tert-Butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (77 mg, 0.30 mmol) was dissolved in 1,4-dioxane (1.5 mL), then to the solution, hexamethylditin (128 mg, 0.390 mmol) and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 1.5 hours. To the reaction mixture, 3-bromo-6-chloro-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine (109 mg, 0.300 mmol) and copper(I) iodide (5.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (32.9 mg, 22%).

MS: m/z 506.2 (M+H)⁺.

Step 3: tert-Butyl N-[2-[6-[6-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate

tert-Butyl N-[2-[6-[6-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate (20 mg, 0.0395 mmol) was dissolved in DMF (0.13 mL), then to the solution, zinc cyanide (2.8 mg, 0.024 mmol), zinc powder (0.3 mg, 4 μmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride-dichloromethane adduct (1.6 mg, 2 μmol) were added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

MS: m/z 497.3 (M+H)⁺.

Step 4: 5-[5-(2-Aminoethyl)pyridin-2-yl]-6-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile

Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (8.6 mg).

Exact MS: 396.2

Obs. MS (M+H)⁺: 397.4

Example 44 6-[5-(Aminomethyl)pyridin-2-yl]-5-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxypyridine-3-carbonitrile (Compound No. 1289)

Step 1: tert-Butyl N-[[6-(5-cyano-3-fluoropyridin-2-yl)pyridin-3-yl]methyl]carbamate

tert-Butyl N-[(6-chloropyridin-3-yl)methyl]carbamate (72.8 mg, 0.300 mmol) was dissolved in 1,4-dioxane (1.5 mL), then to the solution, hexamethylditin (128 mg, 0.390 mmol) and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 1.5 hours. To the reaction mixture, 6-chloro-5-fluoropyridine-3-carbonitrile (51.7 mg, 0.330 mmol) and copper(I) iodide (5.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (77.9 mg, 79%).

MS: m/z 329.2 (M+H)⁺.

Step, 2: tert-Butyl N-[[6-[5-cyano-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxypyridin-2-yl]pyridin-3-yl]methyl]carbamate

tert-Butyl N-[[6-(5-cyano-3-fluoropyridin-2-yl)pyridin-3-yl]methyl]carbamate (77.9 mg, 0.237 mmol) and 2-methyl-5-pyridin-2-yl-4H-pyrazol-3-one (41.6 mg, 0.237 mmol) were dissolved in NMP (0.95 mL), then to the solution, potassium carbonate (65.6 mg, 0.475 mmol) was added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.

Step 3: 6-[5-(Aminomethyl)pyridin-2-yl]-5-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxypyridine-3-carbonitrile

Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (6.9 mg).

Exact MS: 383.2

Obs. MS (M+H)⁺: 384.2

Example 45

Compounds 1 to 1405 shown in Table 1 above were synthesized by protection, deprotection and the like as necessary according to the synthesis methods described in Examples 1 to 44. The MS data is shown in Table 2 below.

TABLE 2 Compound Exact Obs MS number MS (M + H)⁺ 1 377.2 378.1 2 414.2 415.2 3 454.2 455.2 4 428.2 429.4 5 482.2 483.4 6 409.2 410.4 7 415.2 416.2 8 429.2 430.2 9 431.2 432.2 10 470.2 471.3 11 445.2 446.2 12 456.2 457.3 13 507.2 508.2 14 389.2 390.2 15 401.2 402.4 16 429.3 430.5 17 413.2 414.0 18 449.2 450.4 19 449.2 450.4 20 410.2 411.4 21 431.2 431.9 22 422.2 422.9 23 474.2 474.9 24 421.2 422.4 25 399.2 400.2 26 471.2 471.9 27 427.2 428.0 28 409.2 409.9 29 409.2 409.9 30 413.1 413.9 31 429.2 430.0 32 412.1 412.9 33 412.1 412.9 34 397.2 398.4 35 428.1 428.9 36 406.2 406.9 37 442.2 443.4 38 402.2 402.9 39 442.2 443.0 40 413.1 413.8 41 416.2 417.3 42 430.2 431.3 43 414.2 415.3 44 428.2 429.3 45 414.2 415.3 46 398.2 399.2 47 416.2 417.3 48 404.2 405.2 49 414.2 415.3 50 401.2 402.4 51 417.2 418.5 52 427.2 428.5 53 441.2 442.5 54 515.3 516.5 55 499.2 500.5 56 487.2 488.5 57 487.3 488.6 58 473.2 474.5 59 491.2 492.5 60 509.2 510.4 61 509.2 510.5 62 429.2 430.5 63 489.2 490.4 64 489.2 490.2 65 385.2 386.2 66 399.2 400.4 67 441.2 442.3 68 445.2 446.4 69 392.2 393.3 70 408.2 409.0 71 443.1 444.1 72 497.2 498.3 73 481.2 482.3 74 416.2 417.3 75 407.2 408.3 76 351.1 352.2 77 402.2 403.1 78 400.2 401.2 79 351.1 352.2 80 402.2 403.1 81 400.2 401.1 82 408.2 409.3 83 418.2 419.3 84 435.1 436.2 85 416.2 417.3 86 407.2 408.3 87 351.1 352.2 88 351.1 352.0 89 402.2 403.3 90 400.2 401.3 91 402.2 403.3 92 400.2 401.1 93 417.2 418.3 94 435.2 436.3 95 427.2 428.3 96 450.2 451.3 97 476.2 477.2 98 471.2 472.2 99 468.2 469.3 100 459.2 460.2 101 483.2 484.2 102 393.2 394.3 103 393.2 394.3 104 440.2 441.3 105 449.2 450.3 106 459.2 460.3 107 400.2 401.3 108 402.2 403.3 109 414.1 415.2 110 411.2 412.3 111 464.2 465.2 112 424.2 425.3 113 469.2 470.2 114 393.2 394.3 115 394.2 395.3 116 410.2 411.2 117 476.1 477.2 118 422.2 423.2 119 449.2 450.2 120 450.2 451.2 121 436.2 437.2 122 469.2 470.1 123 416.2 417.1 124 416.2 417.1 125 402.2 403.3 126 416.2 417.3 127 432.2 433.2 128 414.2 415.2 129 452.2 453.1 130 424.2 425.2 131 441.2 442.2 132 427.2 428.2 133 465.2 466.2 134 443.2 444.2 135 368.1 369.1 136 421.2 422.1 137 384.2 385.1 138 414.2 415.3 139 451.2 452.2 140 430.2 431.2 141 430.2 431.2 142 426.2 427.2 143 441.2 442.2 144 421.2 422.1 145 401.2 402.2 146 410.1 411.1 147 470.2 471.2 148 470.2 471.2 149 449.2 450.2 150 465.2 466.2 151 499.2 500.2 152 447.2 448.2 153 467.2 468.2 154 398.1 399.1 155 475.2 476.1 156 461.2 462.2 157 445.2 446.2 158 470.2 471.2 159 446.1 447.1 160 395.2 396.3 161 411.2 412.3 162 396.2 397.3 163 395.2 396.3 164 409.2 410.3 165 412.2 413.3 166 408.2 409.3 167 425.2 426.2 168 438.1 439.2 169 421.2 422.3 170 412.2 413.2 171 412.2 413.2 172 415.2 416.3 173 415.2 416.2 174 395.2 396.3 175 395.2 396.3 176 396.2 397.3 177 411.2 412.2 178 396.2 397.3 179 396.2 397.2 180 425.2 426.3 181 410.2 411.3 182 410.2 411.3 183 428.2 429.2 184 413.2 414.3 185 413.2 414.2 186 412.2 413.3 187 413.2 414.3 188 408.2 409.3 189 422.2 423.3 190 425.2 426.2 191 448.2 449.1 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396.2 397.0 1003 395.2 396.0 1004 376.1 377.0 1005 363.1 364.0 1006 395.2 396.0 1007 383.2 384.2 1008 382.2 383.2 1009 397.2 398.2 1010 396.2 397.1 1011 340.2 342.1 1012 341.2 341.1 1013 355.2 356.2 1014 354.2 355.2 1015 339.1 340.1 1016 338.2 339.1 1017 353.2 354.1 1018 352.2 353.1 1019 381.1 382.1 1020 357.1 358.2 1021 371.2 372.2 1022 379.1 380.1 1023 397.1 398.2 1024 392.1 393.2 1025 360.2 361.3 1026 346.2 347.3 1027 417.2 418.4 1028 403.2 404.3 1029 402.2 403.3 1030 374.2 375.4 1031 388.2 389.4 1032 403.2 404.4 1033 386.2 387.5 1034 386.2 387.5 1035 372.2 373.4 1036 372.2 373.4 1037 395.1 396.3 1038 381.1 382.2 1039 403.1 404.1 1040 429.2 430.2 1041 402.2 403.3 1042 428.2 429.3 1043 375.2 376.1 1044 360.2 361.2 1045 346.2 347.2 1046 372.2 373.2 1047 358.2 359.2 1048 401.1 402.1 1049 414.2 415.2 1050 387.1 388.1 1051 361.2 362.2 1052 396.1 397.0 1053 415.2 416.3 1054 360.2 361.2 1055 382.1 383.0 1056 388.2 389.2 1057 372.2 373.1 1058 358.2 359.1 1059 432.2 433.2 1060 374.2 375.2 1061 389.2 390.1 1062 415.2 416.2 1063 401.2 402.1 1064 420.1 421.2 1065 434.2 435.2 1066 419.1 420.1 1067 419.1 420.2 1068 433.2 434.2 1069 420.1 421.1 1070 434.2 435.1 1071 401.2 402.2 1072 387.2 388.2 1073 439.2 440.1 1074 425.2 426.1 1075 360.2 361.1 1076 433.2 434.1 1077 487.1 488.1 1078 488.1 489.1 1079 413.2 414.1 1080 473.1 474.0 1081 402.2 403.1 1082 390.1 391.1 1083 403.2 404.1 1084 404.2 405.1 1085 389.1 390.1 1086 403.2 404.1 1087 474.1 475.1 1088 419.1 420.1 1089 390.1 391.1 1090 391.1 392.1 1091 404.2 407.1 1092 405.2 406.1 1093 406.1 408.1 1094 420.1 421.1 1095 407.1 408.1 1096 421.1 422.1 1097 421.2 422.3 1098 375.1 376.2 1099 361.1 362.2 1100 325.1 326.1 1101 365.2 366.2 1102 353.2 354.2 1103 422.2 423.0 1104 408.2 409.2 1105 396.2 397.0 1106 409.2 410.0 1107 410.2 411.0 1108 365.2 366.2 1109 351.1 352.1 1110 364.2 365.2 1111 378.2 379.3 1112 378.2 379.3 1113 387.2 388.3 1114 401.2 402.3 1115 401.2 402.2 1116 346.2 347.1 1117 388.2 389.2 1118 346.2 347.3 1119 388.2 389.3 1120 392.2 393.2 1121 344.2 345.3 1122 369.2 370.3 1123 370.2 371.3 1124 446.2 447.2 1125 460.2 461.3 1126 388.2 389.2 1127 384.2 384.9 1128 398.2 399.1 1129 394.2 395.2 1130 408.2 409.2 1131 379.2 380.3 1132 379.2 380.3 1133 395.2 396.4 1134 380.2 381.3 1135 380.2 381.2 1136 395.2 396.4 1137 394.2 395.4 1138 395.2 396.4 1139 409.2 410.3 1140 375.2 376.4 1141 376.2 377.4 1142 390.2 391.4 1143 397.2 398.4 1144 413.1 414.3 1145 393.2 394.4 1146 393.2 394.4 1147 397.2 398.4 1148 393.2 394.4 1149 397.2 398.4 1150 393.2 394.4 1151 407.2 408.4 1152 411.2 412.4 1153 407.2 408.4 1154 411.2 412.4 1155 407.2 408.4 1156 411.2 412.4 1157 394.2 395.3 1158 393.2 394.3 1159 373.2 374.3 1160 380.2 381.3 1161 427.2 428.2 1162 428.2 429.2 1163 387.2 388.2 1164 388.2 389.2 1165 417.2 418.3 1166 418.2 419.2 1167 381.2 382.3 1168 367.2 368.2 1169 381.2 382.3 1170 367.2 368.2 1171 360.2 361.3 1172 346.2 347.3 1173 386.1 387.2 1174 372.1 373.2 1175 401.2 402.3 1176 368.2 369.2 1177 433.2 434.3 1178 375.2 376.4 1179 415.2 416.4 1180 483.2 484.4 1181 389.2 390.4 1182 380.2 381.3 1183 366.2 367.2 1184 361.2 362.3 1185 347.2 348.3 1186 387.2 388.3 1187 345.2 346.2 1188 347.2 348.3 1189 333.2 334.2 1190 373.2 374.3 1191 331.2 332.2 1192 399.2 400.2 1193 412.2 413.2 1194 413.2 414.3 1195 360.2 361.0 1196 346.2 347.0 1197 381.2 382.2 1198 373.2 374.2 1199 374.2 375.2 1200 389.2 390.2 1201 380.2 381.1 1202 395.2 396.2 1203 394.2 395.2 1204 414.2 415.3 1205 381.2 382.1 1206 375.2 376.2 1207 389.2 390.2 1208 388.2 389.2 1209 347.2 348.1 1210 373.2 374.2 1211 387.2 388.2 1212 386.2 387.2 1213 387.2 388.2 1214 395.2 396.3 1215 394.2 395.3 1216 361.2 363.3 1217 360.2 361.2 1218 401.2 402.4 1219 400.2 401.4 1220 374.2 375.0 1221 352.2 353.0 1222 353.2 354.1 1223 339.2 340.0 1224 367.2 368.3 1225 353.2 354.3 1226 427.2 428.5 1227 439.2 440.5 1228 425.2 426.2 1229 395.2 396.3 1230 425.2 426.3 1231 409.2 410.3 1232 416.1 417.2 1233 375.2 376.4 1234 376.2 377.2 1235 390.2 391.1 1236 404.2 405.2 1237 429.2 430.2 1238 433.2 434.1 1239 417.2 418.4 1240 415.2 416.4 1241 401.2 402.4 1242 418.2 419.4 1243 416.2 417.4 1244 402.2 403.4 1245 407.2 408.3 1246 405.2 406.4 1247 391.2 392.4 1248 432.2 433.2 1249 430.2 431.3 1250 416.2 417.4 1251 421.2 422.4 1252 419.2 420.3 1253 405.2 406.4 1254 433.2 434.3 1255 431.2 432.4 1256 417.2 418.4 1257 419.2 420.3 1258 417.2 418.3 1259 403.2 404.3 1260 432.2 433.2 1261 418.2 419.2 1262 403.2 404.2 1263 377.1 378.3 1264 388.1 389.2 1265 389.1 390.2 1266 362.1 363.2 1267 363.1 364.2 1268 403.2 404.2 1269 409.1 410.1 1270 423.1 424.2 1271 411.1 412.2 1272 377.1 378.2 1273 391.2 392.3 1274 440.1 441.3 1275 426.1 427.2 1276 433.2 434.3 1277 396.2 397.2 1278 382.2 383.2 1279 396.2 397.4 1280 397.2 398.3 1281 361.2 362.2 1282 400.2 401.5 1283 384.1 385.4 1284 416.2 417.4 1285 403.2 404.2 1286 395.1 396.2 1287 384.1 385.2 1288 382.2 383.3 1289 383.1 384.2 1290 405.1 406.3 1291 391.1 392.2 1292 405.1 406.2 1293 391.1 392.3

Example 46

Evaluation of TRPC6 Channel Inhibitory Activity (1) (Compound Nos. 1-1293)

In order to investigate TRPC6 channel inhibitory activity of the compounds, evaluation was conducted using FLIPR® Calcium 5 Assay Kit (Molecular Devices) in accordance with the following procedure. Human TRPC6 stably-expressing cells were seeded in a 384-well black clear bottom plate at a density of 5×10³/well and cultured in an incubator at 37° C. 5% CO₂ for 24 hours. Thereafter, 25 μL of a Non Wash Dye Solution, prepared using Component A, 20 mM HEPES-HBSS and 250 mM probenecid, all of which are included in the kit, was added to each well, and the plate was incubated for 30 minutes. A volume of 12.5 μL of a compound solution was added into each well while the fluorescence was measured with FLIPR tetra. After 20 minutes, 12.5 μL of a 1-oleoyl-2-acetyl glycerol (OAG) solution was added at a final concentration of 30 μM. The difference between the minimum fluorescence intensity before the addition of the compound and the maximum fluorescence intensity after the addition of OAG was defined as a signal. An inhibition rate was calculated, assuming the average signal of wells without the compound as the inhibition rate of 0% and the average signal of wells without the compound and OAG as the inhibition rate of 100%. The calculated inhibition rate was analyzed by a four-parameter logistic regression to quantify the inhibition rate in the logarithm of the inverse of the effective concentration which gives a 50% inhibition rate (pIC₅₀). The results are shown in the following Table 3. The intensity was expressed by the following symbols (+, ++, +++).

+: pIC₅₀<6.0 ++: 6.0≤pIC₅₀<8.0 +++: 8.0≤pIC₅₀

Example 47

Evaluation of TRPC6 Channel Inhibitory Activity (2) (Compound Nos. 1293 to 1405)

The activity of the TRPC6 inhibitor was measured by stimulating HEK293 cells, in which human TRPC6 was stably introduced, with OAG (1-Oleoyl-2-acetyl-sn-glycerol, Miliipore Sigma, 06754), using the FLIPR tetra system. The cells were proliferated in a humid environment at 37° C. 5% CO₂ using a growth medium (DMEM (Dulbecco's Modified Eagle's Medium) high glucose containing 10% fetal bovine serum, 1×PSGlu (penicillin-streptomycin glutamine), 1×NEAA (Non-essential amino acid), sodium pyruvate and 200 μg/mL hyglomycin. For cell subculture, the cells were proliferated to 70-90% confluence, and gently washed twice with PBS (phosphate-buffered saline) free of calcium and magnesium after removing the medium. Then, the cells were incubated at 37° C. for 5 minutes after adding trypsin (3 mL), peeled off by tapping the flask at the base of the hand, 7 mL of growth medium was added to inactivate trypsin, and then the cells were resuspended. Usually, the cells were separated every 2-3 days to become a cell density of ⅕. The day before evaluation, the cells were seeded in a poly-D-lysine (PDL) coated 384-well plate using a multi-channel pipette or multidrop at a cell density of 1.0-1.5×10⁴ cells/25 μL/well. After culturing overnight in a PDL-coated 384 Blackwell plate, a fluorescent dye buffer was added first to the cells and the cells were cultured at room temperature for 90-120 minutes. For preparing 10 mL of fluorescent dye buffer, 9 mL of assay buffer, 1 mL of 10×PBX signal enhancer, and 10 μL of calcium indicator were mixed. Cells treated with the compounds of each level 25 minutes before the stimulation with OAG of TRPC6 agonist were incubated. OAG solution was prepared by adding OAG to assay buffer (Ca ringer solution base: 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid), 4 mM MgCl₂, 120 mM NaCl, 5 mM KCl, pH=7.2 (25° C.)+0.1% BSA+2 mM CaCl₂)) to give an OAG concentration of 0.2 mM/2% DMSO. The final concentration of OAG added to the cells is 50 μM/0.5% DMSO. A volume of 12.5 μL of OAG solution was added, and activation of TRPC6 channel was measured using the FLIPR tetra system assaying the change in intracellular calcium level as an index. The 180 seconds imaging frame was defined as the background signal, and the subtraction of the background signal from the raw data was used as the fluorescence peak signal. Each fluorescence peak signal is standardized using an OAG-induced signal and buffer-induced signal as 100% and 0%, respectively. The inhibition rate obtained by plotting the peak signal after the addition of the compounds of each level was analyzed by a four-parameter logistic regression to quantify the inhibition rate in the logarithm of the inverse of the effective concentration which gives a 50% inhibition rate (pIC₅₀). The results are shown in the following Table 3. The intensity was expressed by the above-mentioned symbols (+, ++, +++).

TABLE 3 Compound Inhibitory number activity 1 ++ 2 +++ 3 ++ 4 + 5 + 6 +++ 7 +++ 8 + 9 +++ 10 + 11 +++ 12 + 13 ++ 14 + 15 ++ 16 ++ 17 +++ 18 ++ 19 ++ 20 ++ 21 +++ 22 ++ 23 ++ 24 ++ 25 +++ 26 +++ 27 ++ 28 ++ 29 ++ 30 +++ 31 ++ 32 +++ 33 +++ 34 ++ 35 ++ 36 ++ 37 + 38 + 39 + 40 + 41 + 42 + 43 ++ 44 + 45 ++ 46 +++ 47 ++ 48 ++ 49 ++ 50 +++ 51 + 52 ++ 53 ++ 54 + 55 + 56 + 57 + 58 ++ 59 ++ 60 ++ 61 + 62 +++ 63 + 64 + 65 +++ 66 +++ 67 ++ 68 ++ 69 +++ 70 +++ 71 ++ 72 ++ 73 ++ 74 ++ 75 ++ 76 + 77 + 78 ++ 79 + 80 + 81 + 82 +++ 83 + 84 ++ 85 ++ 86 ++ 87 + 88 + 89 + 90 ++ 91 + 92 + 93 +++ 94 + 95 + 96 + 97 + 98 + 99 + 100 +++ 101 +++ 102 ++ 103 ++ 104 + 105 + 106 + 107 ++ 108 ++ 109 + 110 + 111 ++ 112 +++ 113 +++ 114 ++ 115 +++ 116 ++ 117 ++ 118 ++ 119 + 120 +++ 121 + 122 ++ 123 ++ 124 ++ 125 ++ 126 + 127 + 128 + 129 + 130 +++ 131 + 132 ++ 133 +++ 134 ++ 135 + 136 ++ 137 +++ 138 +++ 139 ++ 140 ++ 141 ++ 142 ++ 143 + 144 ++ 145 ++ 146 + 147 ++ 148 ++ 149 +++ 150 +++ 151 ++ 152 ++ 153 +++ 154 ++ 155 ++ 156 ++ 157 +++ 158 ++ 159 +++ 160 +++ 161 +++ 162 +++ 163 ++ 164 +++ 165 ++ 166 ++ 167 ++ 168 ++ 169 + 170 +++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 +++ 177 +++ 178 ++ 179 +++ 180 +++ 181 ++ 182 +++ 183 +++ 184 ++ 185 +++ 186 +++ 187 +++ 188 + 189 + 190 ++ 191 + 192 ++ 193 + 194 + 195 ++ 196 ++ 197 +++ 198 +++ 199 +++ 200 + 201 + 202 +++ 203 ++ 204 +++ 205 +++ 206 +++ 207 ++ 208 + 209 + 210 + 211 +++ 212 +++ 213 +++ 214 ++ 215 +++ 216 ++ 217 + 218 + 219 ++ 220 + 221 ++ 222 ++ 223 ++ 224 ++ 225 +++ 226 +++ 227 +++ 228 +++ 229 +++ 230 +++ 231 +++ 232 +++ 233 +++ 234 + 235 ++ 236 ++ 237 +++ 238 +++ 239 + 240 ++ 241 +++ 242 + 243 + 244 ++ 245 ++ 246 +++ 247 +++ 248 +++ 249 +++ 250 +++ 251 + 252 + 253 +++ 254 +++ 255 ++ 256 ++ 257 ++ 258 +++ 259 ++ 260 +++ 261 +++ 262 +++ 263 ++ 264 +++ 265 ++ 266 +++ 267 +++ 268 ++ 269 ++ 270 ++ 271 ++ 272 +++ 273 +++ 274 +++ 275 +++ 276 +++ 277 +++ 278 +++ 279 + 280 ++ 281 + 282 ++ 283 ++ 284 ++ 285 +++ 286 ++ 287 +++ 288 +++ 289 +++ 290 ++ 291 + 292 ++ 293 +++ 294 +++ 295 +++ 296 +++ 297 ++ 298 ++ 299 +++ 300 ++ 301 +++ 302 ++ 303 ++ 304 + 305 ++ 306 +++ 307 ++ 308 ++ 309 ++ 310 +++ 311 + 312 +++ 313 +++ 314 +++ 315 +++ 316 + 317 +++ 318 +++ 319 +++ 320 +++ 321 +++ 322 ++ 323 ++ 324 +++ 325 +++ 326 +++ 327 +++ 328 +++ 329 +++ 330 + 331 ++ 332 ++ 333 +++ 334 +++ 335 +++ 336 +++ 337 +++ 338 +++ 339 ++ 340 ++ 341 +++ 342 ++ 343 ++ 344 +++ 345 ++ 346 +++ 347 + 348 +++ 349 + 350 ++ 351 ++ 352 ++ 353 ++ 354 ++ 355 + 356 ++ 357 ++ 358 ++ 359 ++ 360 +++ 361 +++ 362 +++ 363 +++ 364 +++ 365 +++ 366 +++ 367 +++ 368 ++ 369 ++ 370 +++ 371 +++ 372 +++ 373 +++ 374 +++ 375 +++ 376 +++ 377 ++ 378 +++ 379 +++ 380 ++ 381 +++ 382 +++ 383 +++ 384 +++ 385 ++ 386 ++ 387 ++ 388 +++ 389 ++ 390 +++ 391 +++ 392 +++ 393 +++ 394 +++ 395 ++ 396 +++ 397 ++ 398 +++ 399 +++ 400 ++ 401 +++ 402 +++ 403 +++ 404 +++ 405 +++ 406 +++ 407 +++ 408 ++ 409 ++ 410 ++ 411 ++ 412 ++ 413 +++ 414 + 415 + 416 + 417 + 418 ++ 419 + 420 ++ 421 ++ 422 ++ 423 ++ 424 + 425 + 426 +++ 427 ++ 428 ++ 429 +++ 430 +++ 431 ++ 432 +++ 433 ++ 434 +++ 435 + 436 + 437 ++ 438 ++ 439 +++ 440 +++ 441 +++ 442 ++ 443 ++ 444 +++ 445 +++ 446 +++ 447 +++ 448 +++ 449 + 450 + 451 + 452 + 453 + 454 +++ 455 + 456 + 457 + 458 +++ 459 +++ 460 + 461 +++ 462 + 463 + 464 + 465 + 466 + 467 +++ 468 + 469 +++ 470 +++ 471 +++ 472 ++ 473 ++ 474 + 475 + 476 ++ 477 +++ 478 ++ 479 + 480 + 481 + 482 +++ 483 +++ 484 +++ 485 +++ 486 + 487 + 488 + 489 + 490 + 491 ++ 492 ++ 493 +++ 494 ++ 495 ++ 496 +++ 497 + 498 +++ 499 +++ 500 +++ 501 +++ 502 +++ 503 +++ 504 + 505 +++ 506 +++ 507 +++ 508 +++ 509 +++ 510 +++ 511 + 512 ++ 513 ++ 514 ++ 515 ++ 516 + 517 +++ 518 ++ 519 ++ 520 ++ 521 +++ 522 +++ 523 ++ 524 ++ 525 +++ 526 +++ 527 +++ 528 ++ 529 +++ 530 +++ 531 +++ 532 +++ 533 + 534 ++ 535 + 536 +++ 537 + 538 ++ 539 ++ 540 + 541 +++ 542 +++ 543 +++ 544 +++ 545 ++ 546 ++ 547 ++ 548 + 549 ++ 550 +++ 551 ++ 552 + 553 + 554 + 555 + 556 ++ 557 ++ 558 ++ 559 ++ 560 ++ 561 ++ 562 +++ 563 + 564 ++ 565 + 566 ++ 567 ++ 568 + 569 + 570 ++ 571 + 572 ++ 573 ++ 574 ++ 575 +++ 576 + 577 ++ 578 ++ 579 ++ 580 ++ 581 + 582 + 583 + 584 + 585 + 586 + 587 +++ 588 ++ 589 ++ 590 + 591 + 592 +++ 593 + 594 + 595 ++ 596 ++ 597 ++ 598 ++ 599 +++ 600 ++ 601 ++ 602 ++ 603 ++ 604 +++ 605 ++ 606 ++ 607 + 608 + 609 +++ 610 +++ 611 + 612 + 613 ++ 614 + 615 + 616 ++ 617 ++ 618 ++ 619 +++ 620 ++ 621 +++ 622 +++ 623 +++ 624 +++ 625 +++ 626 +++ 627 +++ 628 +++ 629 +++ 630 ++ 631 ++ 632 ++ 633 ++ 634 +++ 635 + 636 + 637 +++ 638 ++ 639 + 640 ++ 641 ++ 642 +++ 643 ++ 644 +++ 645 ++ 646 ++ 647 + 648 + 649 ++ 650 ++ 651 +++ 652 +++ 653 ++ 654 + 655 +++ 656 +++ 657 +++ 658 ++ 659 ++ 660 + 661 + 662 ++ 663 ++ 664 ++ 665 + 666 + 667 ++ 668 +++ 669 ++ 670 +++ 671 +++ 672 +++ 673 + 674 ++ 675 ++ 676 + 677 + 678 + 679 + 680 + 681 + 682 ++ 683 + 684 + 685 + 686 + 687 + 688 ++ 689 ++ 690 ++ 691 +++ 692 + 693 ++ 694 ++ 695 +++ 696 +++ 697 +++ 698 ++ 699 + 700 + 701 +++ 702 +++ 703 ++ 704 +++ 705 ++ 706 +++ 707 ++ 708 +++ 709 ++ 710 ++ 711 +++ 712 ++ 713 ++ 714 +++ 715 +++ 716 ++ 717 ++ 718 +++ 719 ++ 720 + 721 + 722 ++ 723 ++ 724 +++ 725 + 726 ++ 727 ++ 728 ++ 729 ++ 730 ++ 731 + 732 ++ 733 + 734 +++ 735 +++ 736 ++ 737 +++ 738 ++ 739 ++ 740 + 741 ++ 742 +++ 743 +++ 744 ++ 745 + 746 + 747 + 748 +++ 749 ++ 750 ++ 751 + 752 ++ 753 + 754 +++ 755 ++ 756 + 757 + 758 +++ 759 +++ 760 +++ 761 + 762 + 763 + 764 ++ 765 +++ 766 + 767 +++ 768 +++ 769 +++ 770 +++ 771 ++ 772 +++ 773 +++ 774 +++ 775 +++ 776 + 777 + 778 + 779 + 780 + 781 + 782 + 783 + 784 + 785 ++ 786 +++ 787 +++ 788 + 789 ++ 790 ++ 791 ++ 792 ++ 793 + 794 ++ 795 +++ 796 ++ 797 + 798 ++ 799 +++ 800 ++ 801 +++ 802 +++ 803 +++ 804 ++ 805 ++ 806 ++ 807 ++ 808 +++ 809 +++ 810 +++ 811 +++ 812 +++ 813 + 814 + 815 ++ 816 + 817 + 818 ++ 819 ++ 820 + 821 ++ 822 +++ 823 +++ 824 ++ 825 ++ 826 +++ 827 +++ 828 +++ 829 ++ 830 ++ 831 + 832 +++ 833 +++ 834 +++ 835 +++ 836 ++ 837 ++ 838 ++ 839 + 840 + 841 + 842 +++ 843 + 844 + 845 + 846 ++ 847 + 848 +++ 849 +++ 850 +++ 851 + 852 + 853 ++ 854 +++ 855 ++ 856 +++ 857 +++ 858 ++ 859 +++ 860 +++ 861 +++ 862 ++ 863 + 864 ++ 865 + 866 +++ 867 + 868 ++ 869 + 870 ++ 871 + 872 +++ 873 +++ 874 +++ 875 +++ 876 +++ 877 +++ 878 +++ 879 + 880 ++ 881 + 882 + 883 ++ 884 ++ 885 + 886 + 887 ++ 888 ++ 889 + 890 ++ 891 ++ 892 ++ 893 + 894 + 895 + 896 ++ 897 + 898 + 899 ++ 900 +++ 901 + 902 ++ 903 +++ 904 +++ 905 +++ 906 +++ 907 +++ 908 +++ 909 +++ 910 +++ 911 ++ 912 +++ 913 +++ 914 +++ 915 +++ 916 +++ 917 ++ 918 + 919 ++ 920 + 921 + 922 + 923 ++ 924 ++ 925 + 926 + 927 ++ 928 ++ 929 + 930 ++ 931 ++ 932 +++ 933 + 934 ++ 935 +++ 936 ++ 937 +++ 938 ++ 939 ++ 940 + 941 + 942 + 943 + 944 ++ 945 +++ 946 ++ 947 + 948 +++ 949 +++ 950 +++ 951 +++ 952 +++ 953 +++ 954 ++ 955 +++ 956 ++ 957 +++ 958 +++ 959 ++ 960 ++ 961 + 962 ++ 963 +++ 964 ++ 965 ++ 966 +++ 967 ++ 968 +++ 969 +++ 970 + 971 + 972 +++ 973 ++ 974 ++ 975 +++ 976 ++ 977 +++ 978 +++ 979 +++ 980 +++ 981 ++ 982 ++ 983 +++ 984 ++ 985 +++ 986 ++ 987 +++ 988 +++ 989 +++ 990 +++ 991 +++ 992 +++ 993 ++ 994 ++ 995 ++ 996 +++ 997 ++ 998 ++ 999 ++ 1000 +++ 1001 +++ 1002 + 1003 ++ 1004 ++ 1005 + 1006 ++ 1007 ++ 1008 ++ 1009 ++ 1010 +++ 1011 +++ 1012 +++ 1013 +++ 1014 +++ 1015 ++ 1016 ++ 1017 +++ 1018 +++ 1019 ++ 1020 ++ 1021 ++ 1022 + 1023 ++ 1024 ++ 1025 +++ 1026 +++ 1027 +++ 1028 +++ 1029 +++ 1030 +++ 1031 +++ 1032 +++ 1033 +++ 1034 ++ 1035 +++ 1036 + 1037 +++ 1038 ++ 1039 ++ 1040 ++ 1041 ++ 1042 +++ 1043 +++ 1044 +++ 1045 +++ 1046 +++ 1047 +++ 1048 +++ 1049 +++ 1050 ++ 1051 +++ 1052 ++ 1053 + 1054 +++ 1055 + 1056 ++ 1057 +++ 1058 +++ 1059 +++ 1060 +++ 1061 +++ 1062 +++ 1063 +++ 1064 ++ 1065 +++ 1066 +++ 1067 + 1068 ++ 1069 + 1070 + 1071 +++ 1072 +++ 1073 +++ 1074 +++ 1075 +++ 1076 +++ 1077 +++ 1078 +++ 1079 +++ 1080 +++ 1081 ++ 1082 + 1083 ++ 1084 ++ 1085 ++ 1086 +++ 1087 +++ 1088 ++ 1089 ++ 1090 + 1091 ++ 1092 ++ 1093 + 1094 ++ 1095 + 1096 ++ 1097 +++ 1098 + 1099 + 1100 + 1101 ++ 1102 ++ 1103 ++ 1104 + 1105 ++ 1106 +++ 1107 +++ 1108 ++ 1109 ++ 1110 +++ 1111 ++ 1112 + 1113 + 1114 + 1115 + 1116 + 1117 ++ 1118 + 1119 ++ 1120 +++ 1121 + 1122 + 1123 + 1124 + 1125 + 1126 + 1127 + 1128 + 1129 +++ 1130 +++ 1131 +++ 1132 ++ 1133 + 1134 + 1135 +++ 1136 + 1137 +++ 1138 ++ 1139 ++ 1140 ++ 1141 ++ 1142 ++ 1143 +++ 1144 +++ 1145 +++ 1146 ++ 1147 +++ 1148 +++ 1149 +++ 1150 +++ 1151 +++ 1152 +++ 1153 +++ 1154 +++ 1155 +++ 1156 +++ 1157 ++ 1158 + 1159 ++ 1160 + 1161 ++ 1162 ++ 1163 ++ 1164 ++ 1165 + 1166 + 1167 +++ 1168 ++ 1169 + 1170 + 1171 ++ 1172 ++ 1173 +++ 1174 ++ 1175 + 1176 ++ 1177 + 1178 + 1179 + 1180 + 1181 + 1182 + 1183 + 1184 +++ 1185 +++ 1186 +++ 1187 +++ 1188 ++ 1189 ++ 1190 ++ 1191 ++ 1192 + 1193 ++ 1194 + 1195 +++ 1196 ++ 1197 ++ 1198 ++ 1199 +++ 1200 ++ 1201 ++ 1202 +++ 1203 +++ 1204 ++ 1205 +++ 1206 +++ 1207 +++ 1208 +++ 1209 ++ 1210 +++ 1211 +++ 1212 +++ 1213 ++ 1214 +++ 1215 +++ 1216 ++ 1217 +++ 1218 +++ 1219 +++ 1220 + 1221 ++ 1222 ++ 1223 + 1224 ++ 1225 ++ 1226 ++ 1227 ++ 1228 ++ 1229 ++ 1230 + 1231 ++ 1232 + 1233 +++ 1234 +++ 1235 ++ 1236 ++ 1237 +++ 1238 + 1239 +++ 1240 +++ 1241 +++ 1242 ++ 1243 +++ 1244 +++ 1245 ++ 1246 ++ 1247 ++ 1248 ++ 1249 +++ 1250 ++ 1251 ++ 1252 ++ 1253 ++ 1254 ++ 1255 +++ 1256 ++ 1257 ++ 1258 +++ 1259 +++ 1260 ++ 1261 + 1262 + 1263 + 1264 ++ 1265 ++ 1266 ++ 1267 + 1268 ++ 1269 + 1270 ++ 1271 + 1272 ++ 1273 ++ 1274 ++ 1275 + 1276 + 1277 ++ 1278 ++ 1279 +++ 1280 +++ 1281 ++ 1282 ++ 1283 + 1284 ++ 1285 + 1286 + 1287 + 1288 + 1289 + 1290 ++ 1291 + 1292 ++ 1293 ++ 1294 + 1295 +++ 1296 +++ 1297 ++ 1298 ++ 1299 +++ 1300 +++ 1301 +++ 1302 +++ 1303 + 1304 +++ 1305 ++ 1306 +++ 1307 + 1308 ++ 1309 ++ 1310 ++ 1311 ++ 1312 +++ 1313 ++ 1314 ++ 1315 ++ 1316 +++ 1317 +++ 1318 ++ 1319 ++ 1320 ++ 1321 ++ 1322 +++ 1323 +++ 1324 +++ 1325 +++ 1326 ++ 1327 ++ 1328 ++ 1329 + 1330 +++ 1331 + 1332 + 1333 ++ 1334 +++ 1335 +++ 1336 ++ 1337 +++ 1338 +++ 1339 +++ 1340 +++ 1341 ++ 1342 ++ 1343 ++ 1344 + 1345 ++ 1346 +++ 1347 ++ 1348 +++ 1349 ++ 1350 +++ 1351 + 1352 ++ 1353 ++ 1354 +++ 1355 ++ 1356 ++ 1357 +++ 1358 ++ 1359 ++ 1360 +++ 1361 +++ 1362 ++ 1363 + 1364 + 1365 + 1366 +++ 1367 +++ 1368 +++ 1369 +++ 1370 ++ 1371 +++ 1372 + 1373 +++ 1374 ++ 1375 ++ 1376 ++ 1377 ++ 1378 ++ 1379 + 1380 +++ 1381 + 1382 ++ 1383 ++ 1384 ++ 1385 ++ 1386 ++ 1387 +++ 1388 ++ 1389 ++ 1390 ++ 1391 ++ 1392 + 1393 ++ 1394 ++ 1395 +++ 1396 ++ 1397 ++ 1398 +++ 1399 + 1400 ++ 1401 ++ 1402 ++ 1403 ++ 1404 +++ 1405 +

INDUSTRIAL APPLICABILITY

The compound of the present invention is used as a pharmaceutical product. 

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[wherein, X¹, X², and X³ are independently CH, N, or CY; At least one of X¹, X², and X³ is CH or CY; Y is a halogen atom, or a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms; R¹ is a cyano group, a fluorine atom, or a chlorine atom; L¹ is —O—, —S—, —SO—, —CH(R¹¹)—, —C(═CH₂)—, —CO—, 1,1-cyclopropylidene group, or —NR¹²—; R¹¹ is a hydrogen atom, a hydroxy group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, or a C₁₋₃ alkoxy group optionally substituted with 1 to 2 cyano groups; R¹² is a hydrogen atom, or a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms; Ar¹ is a nitrogen-containing heteroaryl ring optionally substituted with 1 to 3 R²; R² is independently a halogen atom, a cyano group, or a C₁₋₄ alkyl group optionally substituted with 1 to 3 halogen atoms; R³ is a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, a (C₁₋₃ alkylcarbonyl)amino group, a (C₁₋₆ alkylamino)carbonyl group, a di(C₁₋₃ alkyl)aminocarbonyl group, a (C₁₋₃ alkoxy)carbonyl group, a (C₃₋₈ cycloalkyl)amino group, a (C₃₋₈ heterocycloalkyl)amino group, a C₃₋₈ cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C₃₋₈ cycloalkyloxy group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkyl group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkoxy group optionally substituted with 1 to 6 R³¹, a di(C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a (C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R³², an aryl group optionally substituted with 1 to 4 R³², or a heteroaryl group optionally substituted with 1 to 4 R³²; R³¹ is independently a halogen atom, a hydroxy group, a cyclopropylidene group, a C₃₋₈ cycloalkyl group optionally substituted with 1 to 3 halogen atoms, a 3- to 8-membered heterocycloalkyl group, an oxetanylidene group, a C₁₋₄ alkoxy group, or a 3- to 8-membered cycloalkyloxy group; R³² is independently a halogen atom, a hydroxy group, an acetylamino group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₁₋₃ alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, a cyano group, a carboxy group, a (C₁₋₃ alkoxy)carbonyl group, a (C₁₋₃ alkyl)sulfonyl group, a carboxamide group, or a benzyloxy group; when R² and R³ are bonded to atoms adjacent to each other on Ar¹, R² and R³ may be bonded via a single bond or —O— to form a 5- to 7-membered ring together with the atoms of Ar¹ to which they are bonded; Ar² is an aryl ring optionally substituted with 1 to 4 R⁴, or a heteroaryl ring optionally substituted with 1 to 4 R⁴; R⁴ is independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C₁₋₃ alkyl)amino group, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, or C₁₋₃ alkoxy group; L² is a single bond, a C₁₋₆ alkylene group optionally substituted with 1 to 3 R²¹, a C₃₋₈ cycloalkylene group optionally substituted with 1 to 3 R²¹, or a 4- to 8-membered heterocycloalkylene group optionally substituted with 1 to 3 R²¹; L² may be bonded at any position to Ar² or —NR⁷R⁸ which is located at either end thereof, One sp³ carbon atom at any position of L² may be replaced by a structure of —O— or —NR²²—; R²¹ is independently a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, a C₁₋₆ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₃₋₈ cycloalkyl group, a C₁₋₆ alkoxy group, a (C₁₋₃ alkoxy)C₁₋₃ alkyl group, a (C₁₋₃ alkoxy) C₁₋₃ alkoxy group, a (hydroxy) C₁₋₆ alkyl group, a (carboxy)C₁₋₃ alkyl group, a (carboxy)C₁₋₃ alkoxy group, a (C₁₋₃ alkoxy)carbonyl group, a (C₁₋₃ alkoxycarbonyl)C₁₋₃ alkyl group, a (C₁₋₆ alkylamino)carbonyl group, a di(C₁₋₃ alkyl) aminocarbonyl group, a phenyl group optionally substituted with 1 to 3 halogen atoms, a heteroaryl group optionally substituted with 1 to 3 halogen atoms, or a phenoxy group optionally substituted with 1 to 3 halogen atoms; R²² is a hydrogen atom or a C₁₋₃ alkyl group; L² and R⁷ may be bonded via a single bond, —O—, —S(═O)_(n)—, or —NR²³—, to form a 4- to 8-membered ring containing a nitrogen atom to which L² and R⁷ are bonded, and the ring is optionally substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups; n represents an integer from 0 to 2; R²³ is a hydrogen atom or a C₁₋₃ alkyl group; when L² and R⁴ are bonded to atoms adjacent to each other on Ar², they may be bonded via a single-bond or —O— to form a 5- to 8-membered ring together with the atoms of Ar² to which they are bonded; R⁷ is a hydrogen atom, or C₁₋₃ alkyl group; R⁷ and an atom of Ar² may be bonded via a single bond to form a 5- to 8-membered ring; R⁸ is a hydrogen atom, a C₁₋₆ alkyl group, an adamantyl group, a C₁₋₆ cycloalkyl group, a cyanomethyl group, an oxetanyl group, a (C₁₋₃ alkylamino)carbonylmethyl group, a di(C₁₋₃ alkyl)aminocarbonylmethyl group, a (C₁₋₃ alkylamino)C₁₋₈ alkyl group, a di(C₁₋₃ alkyl)aminoC₁₋₈ alkyl group, a (hydroxy)C₁₋₈ alkyl group, a (carboxy)C₁₋₃ alkyl group, a (C₁₋₃ alkoxycarbonyl)C₁₋₃ alkyl group, or a (C₁₋₃ alkoxy)C₁₋₃ alkyl group; R⁷ and R⁸ may be bonded each other via a single bond, —O—, —S(═O)_(m)—, or —NR⁴¹ to form a 3- to 8-membered ring, and further, the ring is optionally substituted with an amino group, an oxo group, or a C₁₋₃ alkyl group; m represents an integer from 0 to 2; R⁴¹ is a hydrogen atom or a C₁₋₃ alkyl group.]
 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X¹, X², and X³ are CH.
 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is a cyano group.
 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is a fluorine atom.
 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heteroaryl ring of Ar¹ is one of the following groups:


6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L¹ is —O—.
 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L¹ is —CO—.
 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L¹ is —CH₂—.
 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is a methyl group.
 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R³ is a C₃₋₈ cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C₃₋₈ cycloalkyloxy group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkyl group optionally substituted with 1 to 6 R³¹, a C₁₋₆ alkoxy group optionally substituted with 1 to 6 R³¹, a di(C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a (C₁₋₆ alkyl)amino group optionally substituted with 1 to 6 R³¹, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R³², an aryl group optionally substituted with 1 to 4 R³², or a heteroaryl group optionally substituted with 1 to 4 R³.
 11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R³¹ is a halogen atom, a cyclopropylidene group, or a C₁₋₄ alkoxy group.
 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R³² is a halogen atom, a C₁₋₃ alkyl group optionally substituted with 1 to 3 halogen atoms, a C₁₋₃ alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group or a cyano group.
 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl ring of Ar² is


14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L² is a C₁₋₃ alkylene group optionally substituted with 1 to 2 R²¹.
 15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L² is —CH₂—.
 16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L² is —CH₂CH₂—.
 17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R⁷ is a hydrogen atom.
 18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R⁸ is a hydrogen atom.
 19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) is selected from the following (1) to (150): (1) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (2) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (3) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (4) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(5-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile (5) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(4-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile (6) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile (7) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (8) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(2-methylpropyl)pyrazol-3-yl]oxybenzonitrile (9) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (10) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (11) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile (12) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (13) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyridin-4-yl)oxybenzonitrile (14) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile (15) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (16) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (17) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyridin-4-yl)oxybenzonitrile (18) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (19) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile (20) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (21) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile (22) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(6-phenylpyridazin-4-yl)oxybenzonitrile (23) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (24) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (25) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (26) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (27) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile (28) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2,5-dimethylpyrazol-3-yl)oxybenzonitrile (29) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (30) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (31) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-butyl-2-methylpyrazol-3-yl)oxybenzonitrile (32) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (33) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (34) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (35) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (36) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (37) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (38) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (39) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (40) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (41) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (42) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazol-3-yl)oxybenzonitrile (43) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile (44) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (45) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (46) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopentyl-2-methylpyrazol-3-yl)oxybenzonitrile (47) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (48) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile (49) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2S)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile (50) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxybenzonitrile (51) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2R)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile (52) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-4-yl]oxybenzonitrile (53) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile (54) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (55) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl]oxybenzonitrile (56) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-[2-methoxyethyl(methyl)amino]-6-methylpyridin-4-yl]oxybenzonitrile (57) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(propan-2-ylamino)pyridin-4-yl]oxybenzonitrile (58) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile (59) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3S)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile (60) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile (61) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxybenzonitrile (62) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (63) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (64) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyrimidin-4-yl)oxybenzonitrile (65) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (66) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile (67) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxybenzonitrile (68) 4-[5-(aminomethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (69) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile (70) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (71) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (72) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (73) 4-[5-(aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl]oxybenzonitrile (74) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (75) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (76) 4-[5-(aminomethyl)pyridin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)oxybenzonitrile (77) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(5-phenyl-1,3,4-thiadiazol-2-yl)oxy]benzonitrile (78) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (79) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2-methylpropyl)amino]pyrazol-3-yl]oxybenzonitrile (80) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[cyclopropylmethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (81) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propyl)amino]pyrazol-3-yl]oxybenzonitrile (82) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxybenzonitrile (83) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propan-2-yl)amino]pyrazol-3-yl]oxybenzonitrile (84) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (85) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2,2,2-trifluoroethyl)amino]pyrazol-3-yl]oxybenzonitrile (86) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile (87) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (88) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (89) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (90) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (91) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (92) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile (93) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile (94) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile (95) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile (96) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]oxybenzonitrile (97) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[ethyl(propan-2-yl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (98) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(2-methylpropoxy)pyrimidin-4-yl]oxybenzonitrile (99) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(diethylamino)-2-methylpyrimidin-4-yl]oxybenzonitrile (100) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[methyl(propan-2-yl)amino]pyrimidin-4-yl]oxybenzonitrile (101) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile (102) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile (103) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,5-tetrafluoropyrrolidin-1-yl)pyrazol-3-yl]oxybenzonitrile (104) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (105) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (106) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazol-3-yl]oxybenzonitrile (107) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (108) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile (109) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2,2-dimethylpropyl)-3-methylpyrazol-4-yl]oxybenzonitrile (110) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile (111) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-ethyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (112) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)-3-(trifluoromethyl)pyrazol-4-yl]oxybenzonitrile (113) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methyl-1,3-thiazol-5-yl)pyrazol-3-yl]oxybenzonitrile (114) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(5-methyl-1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile (115) 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (116) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazole-3-amine (117) 2-[6-[4-fluoro-2-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (118) 2-[2-[4-fluoro-2-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (119) 2-[2-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (120) 2-[6-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (121) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazole-3-amine (122) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazole-3-amine (123) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazole-3-amine (124) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazole-3-amine (125) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazole-3-amine (126) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N,1-trimethylpyrazole-3-amine (127) 2-[6-[4-fluoro-2-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxyphenyl]pyridin-3-yl]ethanamine (128) [2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methanamine (129) 2-[2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (130) 2-[6-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (131) 2-[6-[2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-fluorophenyl]pyridin-3-yl]ethanamine (132) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile (133) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile (134) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (135) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (136) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (137) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (138) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (139) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (140) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazole-4-carbonyl)benzonitrile (141) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (142) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (143) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (144) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (145) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile (146) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile (147) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (148) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (149) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile (150) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile.
 20. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 21. A pharmaceutical composition having TRPC6 channel inhibitory activity, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 22. A therapeutic or prophylactic agent for nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, or muscular dystrophy, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 